Quinoxaline-containing compounds as hepatitis C virus inhibitors

ABSTRACT

The present invention discloses compounds of formula I and II or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
                         
which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.60/987,958 filed on Nov. 14, 2007 and U.S. provisional application No.61/025,458 filed on Feb. 1, 2008. The contents of the above applicationsare incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel hepatitis C virus (HCV) proteaseinhibitor compounds having antiviral activity against HCV and useful inthe treatment of HCV infections. More particularly, the inventionrelates to quinoxaline-containing compounds, compositions containingsuch compounds and methods for using the same, as well as processes formaking such compounds.

BACKGROUND OF THE INVENTION

HCV is the principal cause of non-A, non-B hepatitis and is anincreasingly severe public health problem both in the developed anddeveloping world. It is estimated that the virus infects over 200million people worldwide, surpassing the number of individuals infectedwith the human immunodeficiency virus (HIV) by nearly five fold. HCVinfected patients, due to the high percentage of individuals inflictedwith chronic infections, are at an elevated risk of developing cirrhosisof the liver, subsequent hepatocellular carcinoma and terminal liverdisease. HCV is the most prevalent cause of hepatocellular cancer andcause of patients requiring liver transplantations in the western world.

There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

Only two approved therapies for HCV infection are currently available.The original treatment regimen generally involves a 3-12 month course ofintravenous interferon-α (IFN-α), while a new approved second-generationtreatment involves co-treatment with IFN-α and the general antiviralnucleoside mimics like ribavirin. Both of these treatments suffer frominterferon related side effects as well as low efficacy against HCVinfections. There exists a need for the development of effectiveantiviral agents for treatment of HCV infection due to the poortolerability and disappointing efficacy of existing therapies.

In a patient population where the majority of individuals arechronically infected and asymptomatic and the prognoses are unknown, aneffective drug would desirably possess significantly fewer side effectsthan the currently available treatments. The hepatitis C non-structuralprotein-3 (NS3) is a proteolytic enzyme required for processing of theviral polyprotein and consequently viral replication. Despite the hugenumber of viral variants associated with HCV infection, the active siteof the NS3 protease remains highly conserved thus making its inhibitionan attractive mode of intervention. Recent success in the treatment ofHIV with protease inhibitors supports the concept that the inhibition ofNS3 is a key target in the battle against HCV.

HCV is a flaviridae type RNA virus. The HCV genome is enveloped andcontains a single strand RNA molecule composed of circa 9600 base pairs.It encodes a polypeptide comprised of approximately 3010 amino acids.

The HCV polyprotein is processed by viral and host peptidase into 10discreet peptides which serve a variety of functions. There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are sixnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease.

The NS3-NS4A protease is responsible for cleaving four sites on theviral polyprotein. The NS3-NS4A cleavage is autocatalytic, occurring incis. The remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5Ball occur in trans. NS3 is a serine protease which is structurallyclassified as a chymotrypsin-like protease. While the NS serine proteasepossesses proteolytic activity by itself, the HCV protease enzyme is notan efficient enzyme in terms of catalyzing polyprotein cleavage. It hasbeen shown that a central hydrophobic region of the NS4A protein isrequired for this enhancement. The complex formation of the NS3 proteinwith NS4A seems necessary to the processing events, enhancing theproteolytic efficacy at all of the sites.

A general strategy for the development of antiviral agents is toinactivate virally encoded enzymes, including NS3, that are essentialfor the replication of the virus. Current efforts directed toward thediscovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause,Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status andEmerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002).

SUMMARY OF THE INVENTION

The present invention relates to quinoxaline-containing compounds andpharmaceutically acceptable salts, esters or prodrugs thereof, andmethods of using the same to treat hepatitis C infection in a subject inneed of such therapy. Compounds of the present invention interfere withthe life cycle of the hepatitis C virus and are also useful as antiviralagents. The present invention further relates to pharmaceuticalcompositions comprising the aforementioned compounds, salts, esters orprodrugs for administration to a subject suffering from HCV infection.The present invention further features pharmaceutical compositionscomprising a compound of the present invention (or a pharmaceuticallyacceptable salt, ester or prodrug thereof) and another anti-HCV agent,such as interferon (e.g., alpha-interferon, beta-interferon, consensusinterferon, pegylated interferon, or albumin or other conjugatedinterferon), ribavirin, amantadine, another HCV protease inhibitor, oran HCV polymerase, helicase or internal ribosome entry site inhibitor.The invention also relates to methods of treating an HCV infection in asubject by administering to the subject a pharmaceutical composition ofthe present invention. The present invention further relates topharmaceutical compositions comprising the compounds of the presentinvention, or pharmaceutically acceptable salts, esters, or prodrugsthereof, in combination with a pharmaceutically acceptable carrier orexcipient.

In one embodiment of the present invention there are disclosed compoundsrepresented by Formulas I or II, or pharmaceutically acceptable salts,esters, or prodrugs thereof:

Wherein

-   -   A is absent or selected from —(C═O)—, —S(O)₂, —C═N—OR₁ or        —C(═N—CN);    -   L₂₀₁ is absent or selected from —C₁-C₈ alkylene, —C₂-C₈        alkenylene, or —C₂-C₈ alkynylene each containing 0, 1, 2, or 3        heteroatoms selected from O, S, or N; substituted —C₁-C₈        alkylene, substituted —C₂-C₈ alkenylene, or substituted —C₂-C₈        alkynylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂        cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkenylene, or substituted —C₃-C₁₂        cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms        selected from O, S or N;    -   M is absent or selected from O, S, SO, SO₂ or NR₁; wherein R₁ is        selected at each occurrence from the group consisting of:        -   (i) hydrogen;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) heterocycloalkyl or substituted heterocycloalkyl;        -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S, or            N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl;    -   L₁₀₁ is absent or selected from —C₁-C₈ alkylene, —C₂-C₈        alkenylene, or —C₂-C₈ alkynylene each containing 0, 1, 2, or 3        heteroatoms selected from O, S, or N; substituted —C₁-C₈        alkylene, substituted —C₂-C₈ alkenylene, or substituted —C₂-C₈        alkynylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂        cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkenylene, or substituted —C₃-C₁₂        cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms        selected from O, S or N;    -   Z₁₀₁ is absent or selected from aryl, substituted aryl,        heteroaryl, or substituted heteroaryl;    -   W₁₀₁ is absent or selected from —O—, —S—, —NR₁—, —C(O)— or        —C(O)NR₁—;    -   X and Y taken together with the carbon atoms to which they are        attached to form a carbocyclic moiety or a heterocyclic moiety.        The carbocyclic or heterocyclic moiety can be selected from        aryl, substituted aryl, heteroaryl, substituted heteroaryl,        cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted        cycloalkenyl, heterocyclic, or substituted heterocylic;    -   or X and Y together can form a C₂-C₈-alkylene group or a        C₂-C₈-heteroalkylene group.    -   R₁₀₁ and R₁₀₂ are independently selected from the group        consisting of:        -   (i) hydrogen, halogen, CN, CF₃, N₃, NO₂, OR₁, SR₁, SO₂R₂,            —NHS(O)₂—R₂, —NH(SO₂)NR₃R₄, NR₃R₄, CO₂R₁, COR₁, CONR₁R₂,            N(R₁)COR₂;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) heterocycloalkyl or substituted heterocycloalkyl;        -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S, or            N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl;    -   R and R′ are each independently selected from the group        consisting of:        -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S, or            N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl, or            substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,            or substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂            alkylcycloalkenyl, or substituted —C₄-C₁₂ alkylcycloalkenyl;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) heterocycloalkyl or substituted heterocycloalkyl;        -   (iv) hydrogen; deuterium;            or R′ is C₁-C₈-alkyl substituted with one or more halogen            atoms, preferably one or more fluorine, chlorine or bromine            atoms. Preferably, R′ is —CHQ₁Q₂, where Q₁ and Q₂ are            independently selected from halogen; preferably F, Cl and            Br;    -   G is selected from —OH, —NHS(O)₂—R₂, —NH(SO₂)NR₃R₄, and NR₃R₄;    -   R₂ is selected from:        -   (i) aryl; substituted aryl; heteroaryl; substituted            heteroaryl        -   (ii) heterocycloalkyl; substituted heterocycloalkyl;        -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S or            N, substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl; heterocylic; substituted            heterocyclic;    -   R₃ and R₄ are independently selected from:        -   (i) hydrogen;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) heterocycloalkyl or substituted heterocycloalkyl;        -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S, or            N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl; heterocyclic, or            substituted heterocyclic;    -   alternatively, R₃ and R₄ are taken together with the nitrogen        they are attached to form a heterocyclic or substituted        heterocyclic;    -   Z is selected from the groups consisting of:        -   (i) hydrogen;        -   (ii) CN;        -   (iii) N₃;        -   (iv) halogen;        -   (v) —NH—N═CHR₁;        -   (vi) aryl, substituted aryl;        -   (vii) heteroaryl, substituted heteroaryl;        -   (viii) —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl,            heterocycloalkyl, substituted heterocycloalkyl;        -   (ix) —C₁-C₆ alkyl containing 0, 1, 2, or 3 heteroatoms            selected from O, S, or N, optionally substituted with one or            more substituent selected from halogen, aryl, substituted            aryl, heteroaryl, or substituted heteroaryl;        -   (x) —C₂-C₆ alkenyl containing 0, 1, 2, or 3 heteroatoms            selected from O, S, or N, optionally substituted with one or            more substituent selected from halogen, aryl, substituted            aryl, heteroaryl, or substituted heteroaryl;        -   (xi) —C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms            selected from O, S, or N, optionally substituted with one or            more substituent selected from halogen, aryl, substituted            aryl, heteroaryl, or substituted heteroaryl;

W is absent, or selected from alkylene, alkenylene, alkynylene, —O—,—S—, —NR₁—, —C(O)NR₁—, or —C(O)—;

m is 0, 1, 2 or 3; preferably 1;

m′ is 0, 1, 2 or 3; preferably 1; and

s is 1, 2, 3 or 4; preferably 1.

In one subset of the compounds of Formulas I and II:

M is absent or selected from O or NR₁;

Z₁₀₁ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

W₁₀₁ is absent, or selected from —O—, —S—, —NH—, —N(Me)—, —C(O)NH—, or—C(O)N(Me)—;

X and Y taken together with the carbon atoms to which they are attachedto form a cyclic moiety which selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, or substitutedheterocylic;

-   -   R₁₀₁, and R₁₀₂ are independently selected from the group        consisting of:        -   (i) hydrogen, halogen, CN, CF₃, NO₂, OR₁, SR₁, —NHS(O)₂—R₂,            —NH(SO₂)NR₃R₄, NR₃R₄, CO₂R¹, COR₁, CONR₁R₂, N(R₁)COR₂;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) heterocycloalkyl or substituted heterocycloalkyl;        -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S, or            N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl;    -   R₃ and R₄ are independently selected from:        -   (i) hydrogen;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl;        -   (iii) heterocycloalkyl or substituted heterocycloalkyl;        -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S, or            N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl; heterocyclic, or            substituted heterocyclic;

W is absent, or selected from alkylene, alkenylene, alkynylene, —O—,—S—, —NH—, —N(Me)—, —C(O)NH—, or —C(O)N(Me)—;

m=0, 1, or 2;

m′=1 or 2; and

s is 1.

In another embodiment, the present invention features pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt, ester or prodrug thereof. In stillanother embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier or excipient. In yet another embodiment of theinvention are methods of treating a hepatitis C infection in a subjectin need of such treatment with said pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by FormulaI or Formula II as described above, or a pharmaceutically acceptablesalt, ester or prodrug thereof, alone or in combination with apharmaceutically acceptable carrier or excipient.

Other embodiments of the invention are compounds represented by FormulaIII or IV:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where R, R′, A, L₂₀₁, M, L₁₀₁, Z₁₀₁, W_(101′) X, Y, R₁₀₁,R_(102′) W, Z, and G are as previously defined.

Other embodiments of the invention are compounds represented by FormulaV or VI:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where Q₁ and Q₂ are independently fluorine, chlorine orbromine, and where R, A, L₂₀₁, M, L₁₀₁, Z₁₀₁, W₁₀₁, X, Y, R₁₀₁,R_(102′), W, Z, and G are as previously defined. In particularlypreferred embodiments, Q₁ and Q₂ are both fluorine.

Another embodiment of the invention is a compound represented by FormulaVII:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where X₁-X₄ are independently selected from —CR₅ and N,wherein R₅ is independently selected from:

-   -   (i) hydrogen; halogen; —NO₂; —CN; N₃; CF₃;    -   (ii) -M-R₄, M is O, S, NH;    -   (iii) NR₃R₄;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   (v) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (vi) heterocycloalkyl or substituted heterocycloalkyl;        where R₃, R₄, R, R′, A, L₂₀₁, M, L₁₀₁, Z₁₀₁, W₁₀₁ and G are as        previously defined.

Another embodiment of the invention is a compound represented by FormulaVIII:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, wherein X₁-X₄ are as defined for Formula VII, and R, A, Q₁,Q₂, L₂₀₁, M, L₁₀₁, Z₁₀₁, W₁₀₁ and G are as previously defined.

Another embodiment of the invention is a compound represented by FormulaIX:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where Y₁-Y₃ are independently selected from CR₅, N, NR₅, Sand O; where R₅, R, R′, A, L₂₀₁, M, L₁₀₁, Z₁₀₁, W₁₀₁ and G are aspreviously defined.

Another embodiment of the invention is a compound represented by FormulaX:

a pharmaceutically acceptable salt, ester or prodrug thereof, alone orin combination with a pharmaceutically acceptable carrier or excipient,where Y₁-Y₃ are as defined for Formula IX, and R, Q₁, Q₂, A, L₂₀₁, M,L₁₀₁, Z₁₀₁, W₁₀₁ and G are as previously defined.

Another embodiment of the invention is a compound represented by FormulaXI:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where R, R′, A, L₂₀₁, M, L₁₀₁ and G are as previouslydefined.

Another embodiment of the invention is a compound represented by FormulaXII:

a pharmaceutically acceptable salt, ester or prodrug thereof, alone orin combination with a pharmaceutically acceptable carrier or excipient,where R, Q₁, Q₂, A, L₂₀₁, M, L₁₀₁ and G are as previously defined.

Another embodiment of the invention is a compound represented by FormulaXIII:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where W₁ is absent or selected from C₁-C₄ alkylene, C₂-C₄alkenylene, C₂-C₄ alkynylene; where R, R′, A, L₂₀₁, M, L₁₀₁, R₁₀₁, R₁₀₂and G are as previously defined.

Another embodiment of the invention is a compound represented by FormulaXIV:

a pharmaceutically acceptable salt, ester or prodrug thereof, alone orin combination with a pharmaceutically acceptable carrier or excipient,where W₁ is as defined for Formula XIII, and R, Q₁, Q₂, A, L₂₀₁, M,L₁₀₁, R₁₀₁, R₁₀₂ and G are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds (Table 1) according to Formula XV wherein R,M-L, Ar, R′ and G are delineated for each example in Table 1.

TABLE 1 (XV)

Example # R M-L Ar R′ G 1.

OH 2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

OH 55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

OH 334.

OH 335.

OH 336.

OH 337.

OH 338.

OH 339.

OH 340.

OH 341.

OH 342.

OH 343.

OH 344.

OH 345.

OH 346.

OH 347.

OH 348.

OH 349.

OH 350.

OH 351.

OH 352.

OH 353.

OH 354.

OH 355.

OH 356.

357.

358.

359.

360.

361.

362.

363.

364.

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379.

380.

381.

382.

383.

384.

385.

386.

387.

388.

389.

390.

391.

392.

393.

394.

395.

396.

397.

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

430.

431.

432.

433.

434.

435.

436.

437.

438.

439.

440.

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

463.

464.

465.

466.

467.

468.

469.

470.

471.

472.

473.

474.

475.

476.

477.

478.

479.

480.

481.

482.

483.

484.

485.

486.

487.

488.

489.

490.

491.

492.

493.

494.

495.

496.

497.

498.

499.

500.

501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

513.

514.

515.

516.

517.

518.

519.

520.

521.

522.

523.

524.

525.

526.

527.

528.

529.

530.

531.

532.

533.

534.

535.

536.

537.

538.

539.

540.

541.

542.

543.

544.

545.

546.

547.

548.

549.

550.

551.

552.

553.

554.

555.

556.

557.

558.

559.

560.

561.

562.

563.

564.

565.

566.

567.

568.

569.

570.

571.

572.

573.

574.

575.

576.

577.

578.

579.

580.

581.

582.

583.

584.

585.

586.

587.

588.

589.

590.

591.

592.

593.

594.

595.

596.

597.

598.

599.

600.

601.

602.

603.

604.

605.

606.

607.

608.

609.

610.

611.

612.

613.

614.

615.

616.

617.

618.

619.

620.

621.

622.

623.

624.

625.

626.

627.

628.

629.

OH 630.

OH 631.

OH 632.

OH 633.

OH 634.

OH 635.

OH 636.

OH 637.

OH 638.

OH 639.

OH 640.

OH 641.

OH 642.

OH 643.

OH 644.

OH 645.

OH 646.

OH 647.

OH 648.

OH 649.

OH 650.

OH 651.

OH 652.

653.

654.

655.

656.

657.

658.

659.

660.

661.

662.

663.

664.

665.

666.

667.

668.

669.

670.

671.

672.

673.

674.

675.

676.

677.

678.

679.

680.

681.

682.

683.

684.

685.

686.

687.

688.

689.

690.

691.

692.

693.

694.

695.

696.

697.

698.

699.

700.

701.

702.

703.

704.

705.

706.

707.

708.

709.

710.

711.

712.

713.

714.

715.

716.

717.

718.

719.

720.

721.

722.

723.

724.

725.

726.

727.

728.

729.

730.

731.

732.

733.

734.

735.

736.

737.

738.

739.

740.

741.

742.

743.

744.

745.

746.

747.

748.

749.

750.

751.

752.

753.

754.

755.

756.

757.

758.

759.

760.

761.

762.

763.

764.

765.

766.

767.

768.

769.

770.

771.

772.

773.

774.

775.

776.

777.

778.

779.

780.

781.

782.

783.

784.

785.

786.

787.

788.

789.

790.

791.

792.

793.

794.

795.

796.

797.

798.

799.

800.

801.

802.

803.

804.

805.

806.

807.

808.

809.

810.

811.

812.

813.

814.

815.

816.

817.

818.

819.

820.

821.

822.

823.

824.

825.

826.

827.

828.

829.

830.

831.

832.

833.

834.

835.

836.

837.

837.

839.

840.

841.

842.

843.

844.

845.

846.

847.

848.

849.

850.

851.

852.

853.

854.

855.

856.

857.

858.

859.

860.

861.

862.

863.

864.

865.

866.

867.

868.

869.

870.

871.

872.

873.

874.

875.

876.

877.

878.

879.

880.

881.

882.

883.

884.

885.

886.

887.

888.

889.

890.

891.

892.

893.

894.

895.

896.

897.

898.

899.

900.

901.

902.

903.

904.

905.

906.

907.

908.

909.

910.

911.

912.

913.

914.

915.

916.

917.

918.

919.

920.

921.

922.

923.

924.

925.

926.

927.

928.

929.

930.

931.

OH 932.

OH 933.

OH 934.

OH 935.

OH 936.

OH 937.

OH 938.

OH 939.

OH 940.

OH 941.

OH 942.

OH 943.

OH 944.

OH 945.

OH 946.

OH 947.

OH 948.

OH 949.

OH 950.

OH 951.

OH 952.

OH 953.

OH 954.

OH 955.

OH 956.

957.

OH 958.

959.

OH 960.

961.

OH 962.

963.

OH 964.

965.

OH 966.

967.

OH 968.

969.

OH 970.

971.

OH 972.

973.

OH 974.

975.

OH 976.

977.

OH 978.

979.

OH 980.

981.

OH 982.

983.

OH 984.

985.

OH 986.

987.

OH 988.

989.

OH 990.

991.

OH 992.

993.

OH 994.

995.

OH 996.

997.

OH 998.

999.

OH 1000.

1001.

OH 1002.

1003.

OH 1004.

1005.

OH 1006.

1007.

OH 1008.

1009.

OH 1010.

1011.

OH 1012.

1013.

OH 1014.

1015.

OH 1016.

1017.

OH 1018.

1019.

OH 1020.

1021.

OH 1022.

1023.

OH 1024.

1025.

OH 1026.

1027.

OH 1028.

1029.

OH 1030.

1031.

OH 1032.

1033.

OH 1034.

1035.

OH 1036.

1037.

OH 1038.

1039.

OH 1040.

1041.

OH 1042.

1043.

OH 1044.

1045.

OH 1046.

1047.

OH 1048.

1049.

OH 1050.

1051.

OH 1052.

1053.

OH 1054.

1055.

OH 1056.

1057.

OH 1058.

1059.

OH 1060.

1061.

OH 1062.

1063.

OH 1064.

1065.

OH 1066.

1067.

OH 1068.

1069.

OH 1070.

1071.

OH 1072.

1073.

OH 1074.

1075.

OH 1076.

1077.

OH 1078.

1079.

OH 1080.

1081.

OH 1082.

1083.

OH 1084.

1085.

OH 1086.

1087.

OH 1088.

1089.

OH 1090.

1091.

OH 1092.

1093.

OH 1094.

1095.

OH 1096.

1097.

OH 1098.

1099.

OH 1100.

1101.

OH 1102.

1103.

OH 1104.

1105.

OH 1106.

1107.

OH 1108.

1109.

OH 1110.

1111.

OH 1112.

1113.

OH 1114.

1115.

OH 1116.

1117.

OH 1118.

1119.

OH 1120.

1121.

OH 1122.

1123.

OH 1124.

1125.

OH 1126.

1127.

OH 1128.

1129.

OH 1130.

1131.

OH 1132.

1133.

OH 1134.

1135.

OH 1136.

1137.

OH 1138.

1139.

OH 1140.

1141.

OH 1142.

1143.

OH 1144.

1145.

OH 1146.

1147.

OH 1148.

1149.

OH 1150.

1151.

OH 1152.

1153.

OH 1154.

1155.

OH 1156.

1157.

OH 1158.

1159.

OH 1160.

1161.

OH 1162.

1163.

OH 1164.

1165.

OH 1166.

1167.

OH 1168.

1169.

OH 1170.

1171.

OH 1172.

1173.

OH 1174.

1175.

OH 1176.

1177.

OH 1178.

1179.

OH 1180.

1181.

OH 1182.

1183.

OH 1184.

1185.

OH 1186.

1187.

OH 1188.

1189.

OH 1190.

1191.

OH 1192.

1193.

OH 1194.

1195.

OH 1196.

1197.

OH 1198.

1199.

OH 1200.

1201.

OH 1202.

1203.

OH 1204.

1205.

OH 1206.

1207.

OH 1208.

1209.

OH 1210.

1211.

OH 1212.

1213.

OH 1214.

1215.

OH 1216.

1217.

OH 1218.

1219.

OH 1220.

1221.

OH 1222.

1223.

OH 1224.

1225.

OH 1226.

1227.

OH 1228.

1229.

OH 1230.

1231.

OH 1232.

1233.

OH 1234.

1235.

OH 1236.

1237.

OH 1238.

1239.

OH 1240.

1241.

OH 1242.

1243.

OH 1244.

OH 1245.

1246.

1247.

OH 1248.

OH 1249.

1250.

1251.

1252.

1253.

OH 1254.

OH 1255.

1256.

1257.

1258.

1259.

1260.

1261.

1262.

1263.

OH 1264.

OH 1265.

1266.

1267.

1268.

1269.

1270.

1271.

OH 1272.

1273.

1274.

1275.

1276.

OH 1277.

1278.

1279.

1280.

1281.

1282.

1283.

1284.

1285.

1286.

1287.

OH 1288.

OH 1289.

1290.

1291.

OH 1292.

OH 1293.

1294.

1295.

1296.

1297.

OH 1298.

OH 1299.

1300.

1301.

1302.

1303.

1304.

1305.

1306.

1307.

OH 1308.

OH 1309.

1310.

1311.

1312.

1313.

1314.

1315.

1316.

1317.

1318.

1319.

1320.

1321.

1322.

1323.

1324.

1325.

1326.

1327.

1328.

1329.

1330.

1331.

1332.

1333.

1334.

1335.

1336.

1337.

1338.

1339.

1340.

1341.

1342.

1343.

1344.

1345.

1346.

1347.

1348.

1349.

1350.

1351.

1352.

1353.

1354.

1355.

1356.

1357.

1358.

1359.

1360.

1361.

1362.

1363.

1364.

1365.

1366.

1367.

1368.

1369.

1370.

1371.

1372.

1373.

1374.

1375.

1376.

1377.

1378.

1379.

1380.

1381.

1382.

1383.

1384.

1385.

1386.

1387.

1388.

1389.

1390.

1391.

1392.

1393.

1394.

1395.

1396.

1397.

1398.

1399.

1400.

1401.

1402.

1403.

1404.

1405.

1406.

1407.

1408.

1409.

1410.

1411.

1412.

1413.

1414.

1415.

1416.

1417.

1418.

1419.

1420.

1421.

1422.

1423.

1424.

1425.

1426.

1427.

1428.

1429.

1430.

1431.

1432.

1433.

1434.

1435.

1436.

1437.

1438.

1439.

1440.

1441.

1442.

1443.

1444.

1445.

1446.

1447.

1448.

1449.

1450.

1451.

1452.

1453.

1454.

1455.

1456.

1457.

1458.

1459.

1460.

1461.

1462.

1463.

1464.

1465.

1466.

1467.

1468.

1469.

1470.

1471.

1472.

1473.

1474.

1475.

1476.

1477.

1478.

1479.

1480.

1481.

1482.

1483.

1484.

1485.

1486.

1487.

1488.

1489.

1490.

1491.

1492.

1493.

1494.

1495.

1496.

1497.

1498.

1499.

1500.

1501.

1502.

1503.

1504.

1505.

1506.

Representative compounds of the invention also include, but are notlimited to, the following compounds (Table 2) according to Formula XVIwherein R, L-Ar, n, R′ and G are delineated for each example in Table 2.

TABLE 2 (XVI)

Example # R L-Ar n R′ G 1507.

4

1508.

4

1509.

4

1510.

3

1511.

3

1512.

3

1513.

2

1514.

2

1515.

2

1516.

1

1517.

1

1518.

1

1519.

4

1520.

4

1521.

4

1522.

3

1523.

3

1524.

3

1525.

2

1526.

2

1527.

2

1528.

1

1529.

1

1530.

1

1531.

4

1532.

4

1533.

4

1534.

3

1535.

3

1536.

3

1537.

2

1538.

2

1539.

2

1540.

1

1541.

1

1542.

1

1543.

4

1544.

4

1545.

4

1546.

3

1547.

3

1548.

3

1549.

2

1550.

2

1551.

2

1552.

1

1553.

1

1554.

1

Representative compounds of the invention also include, but are notlimited to, the following compounds (Table 3) according to Formula XVIIwherein R, L-Ar, n and G are delineated for each example in Table 3.

TABLE 3 (XVII)

Example # R L-Ar n G 1555.

4

1556.

4

1557.

3

1558.

3

1559.

2

1560.

2

1561.

1

1562.

1

1563.

4

1564.

4

1565.

3

1566.

3

1567.

2

1568.

2

1569.

1

1570.

1

1571.

4

1572.

4

1573.

3

1574.

3

1575.

2

1576.

2

1577.

1

1578.

1

1579.

4

1580.

4

1581.

3

1582.

3

1583.

2

1584.

2

1585.

1

1586.

1

The present invention also features pharmaceutical compositionscomprising a compound of the present invention, or a pharmaceuticallyacceptable salt, ester or prodrug thereof.

Compounds of the present invention can be administered as the soleactive pharmaceutical agent, or used in combination with one or moreagents to treat or prevent hepatitis C infections or the symptomsassociated with HCV infection. Other agents to be administered incombination with a compound or combination of compounds of the inventioninclude therapies for disease caused by HCV infection that suppressesHCV viral replication by direct or indirect mechanisms. These includeagents such as host immune modulators (for example, interferon-alpha,pegylated interferon-alpha, interferon-beta, interferon-gamma, CpGoligonucleotides and the like), or antiviral compounds that inhibit hostcellular functions such as inosine monophosphate dehydrogenase (forexample, ribavirin and the like). Also included are cytokines thatmodulate immune function. Also included are vaccines comprising HCVantigens or antigen adjuvant combinations directed against HCV. Alsoincluded are agents that interact with host cellular components to blockviral protein synthesis by inhibiting the internal ribosome entry site(IRES) initiated translation step of HCV viral replication or to blockviral particle maturation and release with agents targeted toward theviroporin family of membrane proteins such as, for example, HCV P7 andthe like. Other agents to be administered in combination with a compoundof the present invention include any agent or combination of agents thatinhibit the replication of HCV by targeting proteins of the viral genomeinvolved in the viral replication. These agents include but are notlimited to other inhibitors of HCV RNA dependent RNA polymerase such as,for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or U.S. Pat. No. 6,348,587B1 or WO0160315 or WO0132153 ornon-nucleoside inhibitors such as, for example, benzimidazole polymeraseinhibitors described in EP 1162196A1 or WO0204425 or inhibitors of HCVprotease such as, for example, peptidomimetic type inhibitors such asBILN2061 and the like or inhibitors of HCV helicase.

Other agents to be administered in combination with a compound of thepresent invention include any agent or combination of agents thatinhibit the replication of other viruses for co-infected individuals.These agent include but are not limited to therapies for disease causedby hepatitis B (HBV) infection such as, for example, adefovir,lamivudine, and tenofovir or therapies for disease caused by humanimmunodeficiency virus (HIV) infection such as, for example, proteaseinhibitors: ritonavir, lopinavir, indinavir, nelfinavir, saquinavir,amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir; reversetranscriptase inhibitors: zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125; integrase inhibitors: L-870812, S-1360, or entry inhibitors:enfuvirtide (T-20), T-1249.

Accordingly, one aspect of the invention is directed to a method fortreating or preventing an infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents selected from the group consisting of a host immunemodulator and a second antiviral agent, or a combination thereof, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Examples of the host immune modulator are, but not limited to,interferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, a cytokine, a vaccine, and a vaccine comprising anantigen and an adjuvant, and said second antiviral agent inhibitsreplication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome.

Further aspect of the invention is directed to a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment an agent orcombination of agents that treat or alleviate symptoms of HCV infectionincluding cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Yet another aspect of the invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the invention, or a pharmaceuticallyacceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, orcombination thereof. An agent that treats patients for disease caused byhepatitis B (HBV) infection may be for example, but not limited thereto,L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combinationthereof. Example of the RNA-containing virus includes, but not limitedto, hepatitis C virus (HCV).

Another aspect of the invention provides a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment one or moreagents that treat patients for disease caused by human immunodeficiencyvirus (HIV) infection, with a therapeutically effective amount of acompound or a combination of compounds of the invention, or apharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, saltof a prodrug, or combination thereof. The agent that treats patients fordisease caused by human immunodeficiency virus (HIV) infection mayinclude, but is not limited thereto, ritonavir, lopinavir, indinavir,nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114,fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir,zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125,L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combinationthereof. Example of the RNA-containing virus includes, but not limitedto, hepatitis C virus (HCV). In addition, the present invention providesthe use of a compound or a combination of compounds of the invention, ora therapeutically acceptable salt form, stereoisomer, or tautomer,prodrug, salt of a prodrug, or combination thereof, and one or moreagents selected from the group consisting of a host immune modulator anda second antiviral agent, or a combination thereof, to prepare amedicament for the treatment of an infection caused by an RNA-containingvirus in a patient, particularly hepatitis C virus. Examples of the hostimmune modulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compound orcompounds of the invention, together with one or more agents as definedherein above, can be employed in pure form or, where such forms exist,in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, orcombination thereof. Alternatively, such combination of therapeuticagents can be administered as a pharmaceutical composition containing atherapeutically effective amount of the compound or combination ofcompounds of interest, or their pharmaceutically acceptable salt form,prodrugs, or salts of the prodrug, in combination with one or moreagents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, further aspect of the invention is directed to a method oftreating or preventing infection caused by an RNA-containing virus,particularly a hepatitis C virus (HCV), comprising administering to apatient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug,salt of a prodrug, or combination thereof, one or more agents as definedhereinabove, and a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those agents that are effective fordiminishing or preventing the progression of hepatitis C relatedsymptoms or disease. Such agents include but are not limited toimmunomodulatory agents, inhibitors of HCV NS3 protease, otherinhibitors of HCV polymerase, inhibitors of another target in the HCVlife cycle and other anti-HCV agents, including but not limited toribavirin, amantadine, levovirin and viramidine.

Immunomodulatory agents include those agents (compounds or biologicals)that are effective to enhance or potentiate the immune system responsein a mammal. Immunomodulatory agents include, but are not limited to,inosine monophosphate dehydrogenase inhibitors such as VX-497(merimepodib, Vertex Pharmaceuticals), class I interferons, class IIinterferons, consensus interferons, asialo-interferons pegylatedinterferons and conjugated interferons, including but not limited tointerferons conjugated with other proteins including but not limited tohuman albumin. Class I interferons are a group of interferons that allbind to receptor type I, including both naturally and syntheticallyproduced class I interferons, while class II interferons all bind toreceptor type II. Examples of class I interferons include, but are notlimited to, [alpha]-, [beta]-, [delta]-, [omega]-, and[tau]-interferons, while examples of class II interferons include, butare not limited to, [gamma]-interferons.

Inhibitors of HCV NS3 protease include agents (compounds or biologicals)that are effective to inhibit the function of HCV NS3 protease in amammal. Inhibitors of HCV NS3 protease include, but are not limited to,those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO2006/000085, WO 2006/007700 and WO 2006/007708 (all by BoehringerIngelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/099316, WO2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO2005/037214 (Intermune) and WO 2005/051980 (Schering), and thecandidates identified as VX-950, ITMN-191 and SCH 503034.

Inhibitors of HCV polymerase include agents (compounds or biologicals)that are effective to inhibit the function of an HCV polymerase. Suchinhibitors include, but are not limited to, non-nucleoside andnucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors ofHCV polymerase include but are not limited to those compounds describedin: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all byBoehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543(Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (JapanTobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidatesXTL-2125, HCV 796, R-1626 and NM 283.

Inhibitors of another target in the HCV life cycle include agents(compounds or biologicals) that are effective to inhibit the formationand/or replication of HCV other than by inhibiting the function of theHCV NS3 protease. Such agents may interfere with either host or HCVviral mechanisms necessary for the formation and/or replication of HCV.Inhibitors of another target in the HCV life cycle include, but are notlimited to, entry inhibitors, agents that inhibit a target selected froma helicase, a NS2/3 protease and an internal ribosome entry site (IRES)and agents that interfere with the function of other viral targetsincluding but not limited to an NS5A protein and an NS4B protein.

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated is combination therapy to treat suchco-infections by co-administering a compound according to the presentinvention with at least one of an HIV inhibitor, an HAV inhibitor and anHBV inhibitor.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise inhibitor(s) of other targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, and internal ribosome entry site (IRES).

According to another embodiment, the pharmaceutical compositions of thepresent invention may further comprise another anti-viral,anti-bacterial, anti-fungal or anti-cancer agent, or an immunemodulator, or another therapeutic agent.

According to still another embodiment, the present invention includesmethods of treating viral infection such as, but not limited to,hepatitis C infections in a subject in need of such treatment byadministering to said subject an effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt, ester, orprodrug thereof.

According to a further embodiment, the present invention includesmethods of treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject an anti-HCV virally effectiveamount or an inhibitory amount of a pharmaceutical composition of thepresent invention.

An additional embodiment of the present invention includes methods oftreating biological samples by contacting the biological samples withthe compounds of the present invention.

Yet a further aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

The cytochrome P450 monooxygenase inhibitor used in this invention isexpected to inhibit metabolism of the compounds of the invention.Therefore, the cytochrome P450 monooxygenase inhibitor would be in anamount effective to inhibit metabolism of the protease inhibitor.Accordingly, the CYP inhibitor is administered in an amount such thatthe bioavailiablity of the protease inhibitor is increased in comparisonto the bioavailability in the absence of the CYP inhibitor.

In one embodiment, the invention provides methods for improving thepharmacokinetics of compounds of the invention. The advantages ofimproving the pharmacokinetics of drugs are recognized in the art (US2004/0091527; US 2004/0152625; US 2004/0091527). Accordingly, oneembodiment of this invention provides a method for administering aninhibitor of CYP3A4 and a compound of the invention. Another embodimentof this invention provides a method for administering a compound of theinvention and an inhibitor of isozyme 3A4 (“CYP3A4”), isozyme 2C19(“CYP2C19”), isozyme 2D6 (“CYP2D6”), isozyme 1A2 (“CYPIA2”), isozyme 2C9(“CYP2C9”), or isozyme 2E1 (“CYP2E1”). In a preferred embodiment, theCYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor thatimproves the pharmacokinetics of the relevant NS3/4A protease may beused in a method of this invention. These CYP inhibitors include, butare not limited to, ritonavir (WO 94/14436), ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, clomethiazole,cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine,fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir,fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944,and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole.

It will be understood that the administration of the combination of theinvention by means of a single patient pack, or patient packs of eachformulation, containing within a package insert instructing the patientto the correct use of the invention is a desirable additional feature ofthis invention.

According to a further aspect of the invention is a pack comprising atleast a compound of the invention and a CYP inhibitor of the inventionand an information insert containing directions on the use of thecombination of the invention. In an alternative embodiment of thisinvention, the pharmaceutical pack further comprises one or more ofadditional agent as described herein. The additional agent or agents maybe provided in the same pack or in separate packs.

Another aspect of this invention is a packaged kit for a patient to usein the treatment of HCV infection or in the prevention of HCV infection,comprising: a single or a plurality of pharmaceutical formulation ofeach pharmaceutical component; a container housing the pharmaceuticalformulation (s) during storage and prior to administration; andinstructions for carrying out drug administration in a manner effectiveto treat or prevent HCV infection.

Accordingly, this invention provides kits for the simultaneous orsequential administration of a NS3/4A protease inhibitor of theinvention and a CYP inhibitor (and optionally an additional agent) orderivatives thereof are prepared in a conventional manner. Typically,such a kit will comprise, e.g. a composition of each inhibitor andoptionally the additional agent (s) in a pharmaceutically acceptablecarrier (and in one or in a plurality of pharmaceutical formulations)and written instructions for the simultaneous or sequentialadministration.

In another embodiment, a packaged kit is provided that contains one ormore dosage forms for self administration; a container means, preferablysealed, for housing the dosage forms during storage and prior to use;and instructions for a patient to carry out drug administration. Theinstructions will typically be written instructions on a package insert,a label, and/or on other components of the kit, and the dosage form orforms are as described herein. Each dosage form may be individuallyhoused, as in a sheet of a metal foil-plastic laminate with each dosageform isolated from the others in individual cells or bubbles, or thedosage forms may be housed in a single container, as in a plasticbottle. The present kits will also typically include means for packagingthe individual kit components, i.e., the dosage forms, the containermeans, and the written instructions for use. Such packaging means maytake the form of a cardboard or paper box, a plastic or foil pouch, etc.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication. Viralinfection may be determined by measuring virus antibody titer in samplesof a biological fluid, such as blood, using, e.g., enzyme immunoassay.Other suitable diagnostic methods include molecular based techniques,such as RT-PCR, direct hybrid capture assay, nucleic acid sequence basedamplification, and the like. A virus may infect an organ, e.g., liver,and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease andhepatocellular carcinoma.

The term “anti-cancer agent” refers to a compound or drug capable ofpreventing or inhibiting the advancement of cancer. Examples of suchagents include cis-platin, actinomycin D, doxorubicin, vincristine,vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol,colchicine, cyclosporin A, phenothiazines or thioxantheres.

The term “anti-fungal agent” shall used to describe a compound which maybe used to treat a fungus infection other than 3-AP, 3-AMP or prodrugsof 3-AP and 3-AMP according to the present invention. Anti-fungal agentsaccording to the present invention include, for example, terbinafine,fluconazole, itraconazole, posaconazole, clotrimazole, griseofulvin,nystatin, tolnaftate, caspofungin, amphotericin B, liposomalamphotericin B, and amphotericin B lipid complex.

The term “antibacterial agent” refers to both naturally occurringantibiotics produced by microorganisms to suppress the growth of othermicroorganisms, and agents synthesized or modified in the laboratorywhich have either bactericidal or bacteriostatic activity, e.g.,β-lactam antibacterial agents, glycopeptides, macrolides, quinolones,tetracyclines, and aminoglycosides. In general, if an antibacterialagent is bacteriostatic, it means that the agent essentially stopsbacterial cell growth (but does not kill the bacteria); if the agent isbacteriocidal, it means that the agent kills the bacterial cells (andmay stop growth before killing the bacteria).

The term “immune modulator” refers to any substance meant to alter theworking of the humoral or cellular immune system of a subject. Suchimmune modulators include inhibitors of mast cell-mediated inflammation,interferons, interleukins, prostaglandins, steroids, cortico-steroids,colony-stimulating factors, chemotactic factors, etc.

The term “C₁-C₆ alkyl,” or “C₁-C₈ alkyl,” as used herein, refer tosaturated, straight- or branched-chain hydrocarbon radicals containingbetween one and six, or one and eight carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl radicals; and examples of C₁-C₈ alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl, octyl radicals.

The term “C₂-C₆ alkenyl,” or “C₂-C₈ alkenyl,” as used herein, denote agroup derived from a hydrocarbon moiety, wherein the hydrocarbon moietyhas at least one carbon-carbon double bond and contains from two to six,or two to eight carbon atoms, respectively. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

The term “C₂-C₆ alkynyl,” or “C₂-C₈ alkynyl,” as used herein, denote agroup derived from a hydrocarbon moiety, wherein the hydrocarbon moietyhas at least one carbon-carbon triple bond and contains from two to six,or two to eight carbon atoms, respectively. Representative alkynylgroups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

The term “C₃-C₈-cycloalkyl”, or “C₃-C₁₂-cycloalkyl,” as used herein,denotes a group derived from a monocyclic or polycyclic saturatedcarbocyclic ring, where the saturated carbocyclic ring compound has from3 to 8, or from 3 to 12, ring atoms, respectively. Examples ofC₃-C₈-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

The term “C₃-C₈-cycloalkenyl”, or “C₃-C₁₂-cycloalkenyl” as used herein,denote a group derived from a monocyclic or polycyclic carbocyclic ringcompound having at least one carbon-carbon double, where the carbocyclicring compound has from 3 to 8, or from 3 to 12, ring atoms,respectively. Examples of C₃-C₈-cycloalkenyl include, but not limitedto, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and the like; and examples ofC₃-C₁₂-cycloalkenyl include, but not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “arylalkyl,” as used herein, refers to a C₁-C₃ alkyl or C₁-C₆alkyl residue attached to an aryl ring. Examples include, but are notlimited to, benzyl, phenethyl and the like.

The term “heteroaryl,” as used herein, refers to a mono-, bi-, ortri-cyclic aromatic radical or ring having from five to ten ring atomsof which at least one ring atom is selected from S, O and N; wherein anyN or S contained within the ring may be optionally oxidized. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroarylalkyl,” as used herein, refers to a C₁-C₃ alkyl orC₁-C₆ alkyl residue attached to a heteroaryl ring. Examples include, butare not limited to, pyridinylmethyl, pyrimidinylmethyl and the like.

The term “substituted” as used herein, refers to independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —NH₂, N₃, protected amino, alkoxy,thioalkoxy, oxo, -halo-C₁-C₁₂-alkyl, -halo-C₂-C₁₂-alkenyl,-halo-C₂-C₁₂-alkynyl, -halo-C₃-C₁₂-cycloalkyl, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH— aryl, —OCONH— heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂— aryl, —NHCO₂—heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₂-C₁₂-alkynyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₂-C₁₂-alkynyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₂-C₁₂-alkynyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH— aryl, —SO₂NH-heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. It is understoodthat the aryls, heteroaryls, alkyls, and the like can be furthersubstituted. In some cases, each substituent in a substituted moiety isadditionally optionally substituted with one or more groups, each groupbeing independently selected from —F, —Cl, —Br, —I, —OH, —NO₂, —CN, or—NH₂. When there is at least two replacements of the hydrogen atoms withsubstituents, the two substitutents can be taken together to form acycloalkyl, cycloalkenyl or heterocyclic ring.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can also be an aliphatic group, analicyclic group or a heterocyclic group. An “aliphatic group” isnon-aromatic moiety that may contain any combination of carbon atoms,hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, andoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may be used in placeof the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylenegroups described herein.

The term “alicyclic,” as used herein, denotes a group derived from amonocyclic or polycyclic saturated carbocyclic ring compound. Examplesinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Suchalicyclic groups may be further substituted.

The term “heterocycloalkyl” and “heterocyclic” can be usedinterchangeably and refer to a non-aromatic 3-, 4-, 5-, 6- or 7-memberedring or a bi- or tri-cyclic group fused system, where (i) each ringcontains between one and three heteroatoms independently selected fromoxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 doublebonds and each 6-membered ring has 0 to 2 double bonds, (iii) thenitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to a benzene ring, and (vi) the remaining ring atomsare carbon atoms which may be optionally oxo-substituted. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, andtetrahydrofuryl. Such heterocyclic groups may be further substituted togive substituted heterocyclic.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be monovalent or divalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkenylene, arylalkylene, hetoerarylalkylene andheterocycloalkylene groups are to be included in the above definitions,and are applicable to provide the formulas herein with proper valency.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxy group sothat it will depart during synthetic procedures such as in asubstitution or elimination reactions. Examples of hydroxy activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxy activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques, which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxy protecting groups include benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃). Berge, et al. describes pharmaceutically acceptable salts indetail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or separately by reacting the free basefunction with a suitable organic acid. Examples of pharmaceuticallyacceptable salts include, but are not limited to, nontoxic acid additionsalts e.g., salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc. delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired bridged macrocyclic products of the presentinvention. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject such as a human orlower mammal by administering to the subject an anti-hepatitis C virallyeffective amount or an inhibitory amount of a compound of the presentinvention, in such amounts and for such time as is necessary to achievethe desired result. An additional method of the present invention is thetreatment of biological samples with an inhibitory amount of a compoundof composition of the present invention in such amounts and for suchtime as is necessary to achieve the desired result.

The term “anti-hepatitis C virally effective amount” of a compound ofthe invention, as used herein, mean a sufficient amount of the compoundso as to decrease the viral load in a biological sample or in a subject(e.g., resulting in at least 10%, preferably at least 50%, morepreferably at least 80%, and most preferably at least 90% or 95%,reduction in viral load). As well understood in the medical arts, ananti-hepatitis C virally effective amount of a compound of thisinvention will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the hepatitis C viral load in abiological sample or a subject (e.g., resulting in at least 10%,preferably at least 50%, more preferably at least 80%, and mostpreferably at least 90% or 95%, reduction in viral load). It isunderstood that when said inhibitory amount of a compound of the presentinvention is administered to a subject it will be at a reasonablebenefit/risk ratio applicable to any medical treatment as determined bya physician. The term “biological sample(s),” as used herein, means asubstance of biological origin intended for administration to a subject.Examples of biological samples include, but are not limited to, bloodand components thereof such as plasma, platelets, subpopulations ofblood cells and the like; organs such as kidney, liver, heart, lung, andthe like; sperm and ova; bone marrow and components thereof; or stemcells. Thus, another embodiment of the present invention is a method oftreating a biological sample by contacting said biological sample withan inhibitory amount of a compound or pharmaceutical composition of thepresent invention.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. Ingeneral, treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

-   -   ACN for acetonitrile;    -   BME for 2-mercaptoethanol;    -   BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium        hexafluorophosphate;    -   COD for cyclooctadiene;    -   DAST for diethylaminosulfur trifluoride;    -   DABCYL for        6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;    -   DCM for dichloromethane;    -   DIAD for diisopropyl azodicarboxylate;    -   DIBAL-H for diisobutylaluminum hydride;    -   DIEA for diisopropyl ethylamine;    -   DMAP for N,N-dimethylaminopyridine;    -   DME for ethylene glycol dimethyl ether;    -   DMEM for Dulbecco's Modified Eagles Media;    -   DMF for N,N-dimethyl formamide;    -   DMSO for dimethylsulfoxide;    -   DUPHOS for

-   -   EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;    -   EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide        hydrochloride; EtOAc for ethyl acetate;    -   HATU for O(7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate;    -   Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene)        (tricyclohexylphosphine)ruthenium(II);    -   KHMDS is potassium bis(trimethylsilyl) amide;    -   Ms for mesyl;    -   NMM for N-4-methylmorpholine;    -   PyBrOP for Bromo-tri-pyrrolidino-phosphonium        hexafluorophosphate;    -   Ph for phenyl;    -   RCM for ring-closing metathesis;    -   RT for reverse transcription;    -   RT-PCR for reverse transcription-polymerase chain reaction;    -   TEA for triethyl amine;    -   TFA for trifluoroacetic acid;    -   THF for tetrahydrofuran;    -   TLC for thin layer chromatography;    -   TPP or PPh₃ for triphenylphosphine;    -   tBOC or Boc for tert-butyloxy carbonyl; and    -   Xantphos for        4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not to limitthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

The preparation of quinoxalinyl macrocyclic core compounds isexemplified in Scheme 1A. Commercially available Boc-hydroxyproline 1-1was coupled with quinoxaline derivative 1-2 (for the preparation ofquinoxaline analogs, see Schemes 3-6) under Mitsunobu conditions givingcompound 1-3. Attachment at the carbonyl oxygen was observed to form thedesired compound. A detailed discussion of the identification andcharacterization of the unexpected oxo Mitosunobu addition productappears in the examples herein. For further details on the Mitsunobureaction, see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org.React. 29, 1-162 (1983); D. L. Hughes, Organic Preparations andProcedures Int. 28, 127-164 (1996); and J. A. Dodge, S. A. Jones, RecentRes. Dev. Org. Chem. 1, 273-283 (1997). Introduction of vinyl group wasaccomplished via Suzuki (vinylborate/palladium) or Still(vinyltin/Palladium) reaction to afford compound 1-4. Deprotection of1-4 with HCl followed by coupling reaction (HATU/DMF) withBoc-L-tert.-leucine gave compound 1-5. Deprotection of 1-5 with HClfollowed by reacting with 3-butenyl chloroformate resulted in themacrocyclic compound precursor 1-6. Alternatively, compound 1-6 can beprepared from the direct coupling of intermediate 1-4 (afterdeprotection of Boc group) with the corresponding carbamate aminoacid7-3 (for the preparation of the carbamate aminoacid derivatives seeScheme 7). Ring-closing metathesis of compound 1-6 with aruthenium-based catalyst gives the desired macrocyclic intermediate 1-7(for further details on ring closing metathesis see recent reviews:Grubbs et al., Acc. Chem. Res., 1995, 28, 446; Shrock et al.,Tetrahedron 1999, 55, 8141; Furstner, A. Angew. Chem. Int. Ed. 2000, 39,3012; Trnka et al., Acc. Chem. Res. 2001, 34, 18, and Hoveyda et al.,Chem. Eur. J. 2001, 7, 945).

An alternate route to quinoxaline core structures is set forth in Scheme1B, which illustrates the displacement reaction of a substitutedquinoxaline halide with amino-protected hydroxyproline in the presenceof base, such as NaH or NaO^(t)Bu. In this scheme, PG is an aminoprotecting group, Q is a halogen, preferably bromine, chlorine oriodine, X and Y have the meanings given for these variables in FormulaI, W′ has the meanings given for L₁₀₁-W₁₀₁- in Formula I and Z-W— inFormula II and R is hydrogen or alkyl.

The syntheses of quinoxalinyl macrocyclic compounds as HCV proteaseinhibitors are exemplified in Scheme 2. Hydrolysis of compound 1-7 givesthe corresponding carboxylic acid 1-8, which is coupled with aminosulfinimide or amino acid ester 1-9 (for the preparation, see Schemes 8and 9) to afford compound 1-10 or ester 1-11. Hydrolysis of 1-11 gives1-12. Compound 1-10 can also be prepared from the acid 1-12 as shown inscheme 2. Hydrogenation of 1-7 gives compound 1-13, which is transformedinto compounds 1-14 and 1-16 using the same chemistry as in thepreparation of compounds 1-10 and 1-12.

Various quinoxaline derivatives of compound 1-2 (i.e. formula 3-3) canbe made via the condensation of phenyl diamines of formula 3-1, whereinR₆ is previously defined, with keto acids or esters of formula 3-2,wherein R₇ is W-Z as previously defined, in anhydrous methanol at roomtemperature (see Bekerman et al., J. Heterocycl. Chem. 1992, 29, 129-133for further details of this reaction). Examples of phenyl diaminessuitable for creating quinoxaline derivatives of formula 3-3 include,but are not limited to, 1,2-diamino-4-nitrobenze, o-phenylenediamine,3,4-diaminotoluene, 4-chloro-1,2-phenylenediamine,methyl-3,4-diaminobenzoate, benzo[1,3]dioxole-5,6-diamine,1,2-diamino-4,5-methylene dioxybenzene,4-chloro-5-(trifluoromethyl)-1,2-benzenediamine, and the like. Examplesof keto acids suitable for the reaction described in Scheme 3 include,but are not limited to, benzoylformic acid, phenylpyruvic acid,indole-3-glyoxylic acid, indole-3-pyruvic acid, nitrophenylpyruvic acid,(2-furyl)glyoxylic acid, and the like. Examples of keto esters suitablefor the reaction described in Scheme 3 include, but are not limited toethyl thiophene-2-glyoxylate, ethyl 2-oxo-4-phenylbutyrate, ethyl2-(formylamino)-4-thiazolyl glyoxylate, ethyl-2-amino-4-thiozolylglyoxylate, ethyl-2-oxo-4-phenylbutyrate,ethyl-(5-bromothien-2-yl)glyoxylate, ethyl-3-indolylglyoxylate,ethyl-2-methylbenzoyl formate, ethyl-3-ethylbenzoyl formate,ethyl-3-ethylbenzoyl formate, ethyl-4-cyano-2-oxobutyrate,methyl(1-methylindolyl)-3-glyoxylate, and the like.

3,6-substituted quinoxalin-2-ones of formula 4-4, wherein R₇ is W-Z aspreviously defined, can be made in a regioselective manner to favor the6-position substitution beginning with the amide coupling of4-methoxy-2-nitro aniline 4-1 and substituted glyoxylic acid 4-2 toyield compound 4-3. The 3,6-substituted quinoxalin-2-one 4-4 was createdvia catalytic reduction of the nitro of compound 4-3 followed bycondensation. Other substituents may be introduced into 4-4 through theuse of other 2-nitroanilines. Examples of keto acids suitable for thereaction described in Scheme 4 include, but are not limited to,benzoylformic acid, phenylpyruvic acid, indole-3-glyoxylic acid,indole-3-pyruvic acid, nitrophenylpyruvic acid, (2-furyl)glyoxylic acid,and the like. Examples of 2-nitro anilines suitable for the reactiondescribed in Scheme 4 include, but are not limited to,4-ethoxy-2-nitroaniline, 4-amino-3-nitrobenzotrifluoride,4,5-dimethyl-2-nitroaniline, 4-fluoro-2-nitroaniline,4-chloro-2-nitroaniline, 4-amino-3-nitromethylbenzoate,4-benzoyl-2-nitroaniline, 3-bromo-4-methoxy-2-nitroaniline,3′-amino-4′-methyl-2-nitroacetophenone,5-ethoxy-4-fluoro-2-nitroaniline, 4-bromo-2-nitroaniline,4-(trifluoromethoxy)-2-nitroaniline, ethyl-4-amino3-nitrobenzoate,4-bromo-2-methyl-6-nitroaniline, 4-propoxy-2-nitroaniline,5-(propylthio)-2-nitroaniline, and the like.

The 3-substituted 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acidintermediate 5-4 can be formed via condensation of ethyl3,4-diaminobenzoate (5-1) with oxo acetic acid of formula 5-2, whereinR₇═W-Z as previously defined, using the method described previously inScheme 3 (see Bekerman et al., J. Heterocycl. Chem. 1992, 29, 129-133for further details). The resulting ethyl ester 5-3 was then hydrolyzedwith LiOH in MeOH at room temperature to yield carboxylic acidintermediate 5-4.

Carboxylic acid 5-4 then may be converted to substituted ketone 5-6(wherein R₁ is as previously defined) via Weinreb's amide 5-5 andsubsequent treatment with various Grignard Reagents (see Weinreb et al.Tetrahedron Lett. 1977, 33, 4171; Weinreb et al, Synth. Commun. 1982,12, 989 for details of the formation and use of Weinreb's amide; and seeB. S. Furniss, A. J. Hannaford, P. W. G Smith, A. R. Tatchell, Vogel'sTextbook of Practical Organic Chemistry, 5^(th) ed., Longman, 1989). Theaddition was performed in an inert solvent, generally at lowtemperatures. Suitable solvents include, but are not limited to,tetrahydrofuran, diethylether, 1,4-dioxane, 1,2-dimethoxyethane, andhexanes. Preferably the solvent was tetrahydrofuran or diethylether.Preferably the reaction was carried out at −78° C. to 0° C.

Alternatively, carboxylic acid 5-4 may be used to form various amides offormula 5-7, wherein R₄ is as previously defined, in a manner generallydescribed in Scheme 5. All of the various quinoxalin-2-one compoundsdescribed in Scheme 5 are further coupled to the macrocyclic precursorvia the Mitsunobu conditions described above.

Further 6-substituted quinoxalin-2-one compounds can be made via thegeneral procedures set forth in Scheme 6.

A. Reduction of 6-nitro and Amide Formation

6-nitro-1H-quinoxalin-2-one (6-3) can be formed in the manner previouslydescribed from 3,4-diaminonitrobenzene and the oxo acetic acid offormula 6-2, wherein R₇═W-Z as is previously described. Reduction of thenitro group at the 6-position can be achieved via Pd/C with H₂NNH₂.H₂Oin refluxing MeOH. The 6-position of amine 6-4 then can be treated witha wide array of acid chlorides to give various amides of formula 6-5where R₁ is as previously defined.

B. Oxidation of Benzyl alcohol and Reductive Amination

Quinoxalin-2-one of formula 6-7 can be formed via the condensation of3,4-diaminobenzyl alcohol and various oxo acetic acids of formula 6-2,wherein R₇═W-Z as is previously described. The resulting benzyl alcohol6-7 may then be oxidized under Swern conditions, or any other oxidationconditions, to generate aldehyde of formula 6-8. For further detailsconcerning the Swern reaction see A. J. Mancuso, D. Swern, Synthesis1981, 165-185 passim; T. T. Tidwell, Org. React. 1990, 39, 297-572passim. For other oxidation conditions see B. S. Furniss, A. J.Hannaford, P. W. G. Smith, A. R. Tatchell, Vogel's Textbook of PracticalOrganic Chemistry, 5^(th) ed., Longman, 1989. Subsequent reductiveamination reactions with primary or secondary amines in the presence ofNaCNBH₃ and acetic acid can yield compounds of formula 6-9 wherein R₄and R₅ are as previously defined.

The preparation of carbamate amino acids 7-3 is shown in Scheme 7; n isan integer from 0 to 5. The corresponding olefin alcohol reacts withtriphosphogen in presence of DIPEA, followed by adding the appropriateamino acids 7-2 to give the desired carbamate aminoacids 7-3.

The synthesis of difluoromethyl PI amino acid derivatives 8-5 (i.e. 1-9with R=OEt and R′=CF₂H) is outlined in Scheme 8. Mono-Boc amino acidester was further protected as bis-Boc aminoacid ester 8-2. Oxidativecleavage of compound 8-2 resulted in the aldehyde 8-3, which was thenconverted to difluoromethyl compound 8-4 using aminosulfur trifluoridederivatives such as diethylminosulfur trifluoride (DAST). Deprotectionof 8-4 using HCl afforded the desired difluoromethyl P1 compound 8-5.

Difluoromethyl P1 sulfonamide derivative 9-3 (i.e. 1-9 with R═NHS(O)₂R″and R′═CF₂H) was prepared as shown in Scheme 9. The hydrolysis ofcompound 8-2 gave the acid 9-1, which was converted to 2-2 usingCDI/R″SO₂NH₂/DBU or EDC/DMAP/R″SO₂NH₂. Deprotection of 9-2 afforded thedesired intermediate 9-3.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=OH

Step 1A

A mixture of compound 1a-1 (0.84 g, 7.77 mmol), 1,2-diaminobenzene (2 g,7.77 mmol) and ethanol (10m) was heated under reflux for 2 h, cooled toroom temperature, filtered, washed with cold ethanol and dried underreduced pressure to afford compound 1a (2.12 g) directly used in nexsstep.

Step 1B

To a mixture of the above 1a (1.02 g, 3.39 mmol),Boc-L-cis-hydroxyproline methyl ester (0.831 g, 3.38 mmol) andtriphenylphosphine (1.8 g, 6.86 mmol) in THF at 0° C. was added dropwiseDIAD (1.33 ml, 6.76 mmol). The resulting mixture was held at 0° C. for15 min. before being warmed to room temperature. After 18 hours, themixture was concentrated under vacuum and the residue was purified bychromatography (Hexane/EtOAC=1:0 to 4:1) to give 1b (1.74 g). MS (ESI):m/e 528.02 (M+H).

Alternatively, intermediate 1b was prepared from 1-2 as shown below:

A 12 L round bottom flask was charged with Boc-trans-4-hydroxyproline(141 g, 0.61 mol), THF (3.3 L). The mixture was cooled to 0° C., asolution of NaOtBu (175.9 g, 1.83 mol) in DMF (0.8 L) was added slowlyvia addition funnel while the internal temperature did not exceed 10° C.The ice bath was removed and the mixture was stirred at room temperaturefor 1.5 h. The reaction flask was placed again at 0° C., and compound1-2 (195 g, 0.61 mol) was added portion wise. Thin layer chromatographyshowed no starting material left after 2 h. The reaction mixture wasquenched with water (2 L) and concentrated to remove most of the THF.Another 2 L of water was added, and the mixture was extracted witht-butylmethyl ether twice (4 L+3 L). 4 L of EtOAc was added to theaqueous layer, 10% citric acid was added slowly to adjust the pH to 4-5.Two phases were separated, the aqueous layer was extracted with EtOAc(2×3 L). The combined organic layers were washed with brine, dried overMgSO₄ and concentrated to afford a brown oil (356 g). This crudematerial was dissolved in MeOH/CH₂Cl₂ (1.5 L/1.6 L), cooled to 0° C.,and Me₃SiCH₂N₂ (2M in hexane, 640 mL, 1.28 mol) was added dropwise.After 3.5 h the addition was completed and thin layer chromatographyshowed starting material left. The reaction mixture was concentrated andthe residue was crystallized from MeOH (˜500 mL) to yield 275 g ofcompound 1b. The mother liquor was purified with silica gel column toafford 22 g more of the product. (combined yield: 88% from 1-2).

Step 1C

To a mixture of compound 1b (0.6 g, 1 mmol), potassiumvinyltrifluoroborate (0.52 g, 2 mmol), triethylamine (0.55 ml) andethanol (20 ml) was added 1,1′-bis(diphenylphopshino)ferrocene palladium(II) chloride complex with CH₂Cl₂ (40 mg, 0.048 mmol). The resultingmixture was stirred at 75° C. for 15 h, cooled to room temperature,quenched with 10% KHSO4 aq. solution, extracted with ethyl acetate (3×).The combined organic layers were dried (MgSO4), concentrated undervacuum, and the residue was purified by chromatography (Hexane/EtOAC=1:0to 4:1) to give 1c (0.49 g). MS (ESI): m/z 476.21 (M+H).

Step 1D

A solution of compound 1c (1 mmol) in dichloromethane (2 ml) was treatedwith 4M HCl/dioxane (4 ml, 16 mmol). The resulting mixture was stirredat room temperature for 1 hour, and concentrated in vacuo to dryness toafford HCl salt of compound 1d (100%). MS (ESI): m/e 376.15 (M+H).

Step 1E

To a solution of compound 1d (HCl salt, 100 mg, 0.223 mmol),Boc-L-t-leucine (67 mg, 0.29 mmol) and DIPEA (0.24 ml, 1.37 mmol) in DMF(3 ml) at 0° C. was added HATU (110 mg, 0.29 mmol). The mixture wasstirred at rt for 18 h, diluted with EtOAc and washed with half-sat.-aq.NaCl four times. The organic phase was dried over anhydrous MgSO₄,filtered, and then concentrated in vacuo. The residue was purified bysilica gel chromatography (Hexane/EtOAC=9:1 to 4:1) to afford compound1e (128 mg). MS (ESI): m/e 589.44 (M+H), 489.36 (M-Boc).

Step 1F

A solution of compound 1e (117 mg, 0.2 mmol) in dichloromethane (1 ml)was treated with 4M HCl/dioxane (3 ml, 12 mmol). The resulting mixturewas stirred at room temperature for 1 hour, and concentrated in vacuo todryness to afford HCl salt of compound 1f (100%). MS (ESI): m/z 489.45(M+H).

Step 1G

Compound 1f (0.198 mmol) was dissolved in dichloromethane (3 m), cooledto 0° C., treated with triethylamine (120 ul, 4 eq.) followed by3-butenyl chloroformate (0.041 ml, 0.33 mmol). The mixture was stirredat room temperature for 0.5 to 1 hour, diluted with ethyl acetate,washed with half-sat.-aq. NaCl twice, dried (MgSO4) and concentrated invacuo. The residue was purified by silica gel chromatography(Hexanes/EtOAc=6:1 to 4:1) to give compound 1 g (95 mg). MS (ESI): m/z587.47 (M+H).

Alternatively, compound 1 g was prepared from the coupling of compound1d and 1g-1 as shown below:

To a solution of compound 1d (HCl salt, 10.78 mmol), 1g-1 (2.97 g, 13.12mmol) and DIPEA (5.6 ml, 32.3 mmol) in DMF (30 ml) at 0° C. was added inportions HATU (5.12 g, 13.5 mmol). The mixture was stirred at rt for 18h, diluted with EtOAc and washed with half-sat.-aq. NaCl four times. Theorganic phase was dried over anhydrous MgSO₄, filtered, and thenconcentrated in vacuo. The residue was purified by silica gelchromatography (Hexane/EtOAC=9:1 to 4:1) to afford compound 1g (6.1 g).

Step 1H

To a solution of compound 1g (95 mg, 0.16 mmol) in dichloromethane (20ml) was added Hoveyda-Grubbs' 1^(st) generation catalyst or a similarcatalyst (5 mol % eq.). The reaction mixture was stirred at 40° C. for20 h. The solvent was then evaporated and the residue was purified bysilica gel flash chromatography using gradient elution (Hexane/EtOAC=9:1to 7:3) to yield the macrocyclic compound 1h (58 mg). MS (ESI) m/z559.30 (M+H).

Step 1I

To a solution of compound 1h (58 mg, 0.103 mmol) in THF/MeOH (3 ml/1.5ml) was added 1N lithium hydroxide (1.5 ml, 1.5 mmol). The mixture wasstirred at room temperature for 20 hours. Most organic solvents wereevaporated in vacuo, and the resulting residue was diluted with waterand acidified to pH 5 to 6. The mixture was extracted with EtOAc threetimes. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford 1i (100%). MS (ESI): m/z 545.24 (M+H),551.25 (M+Li).

Step 1J

To a solution of compound 1j-1 (6.6 g, 25.85 mmol) in THF (115 ml) at−78° C. was added slowly NaHMDS (1.0M in THF, 28.5 ml, 28.5 mmol). Afterthe mixture was stirred at −78° C. for an hour, Boc2O (6.8 g, 1.2 eq.)in THF (15 ml) was added. The resulting mixture was stirred, and thetemperature allowed to rise gradually to rt overnight. The reactionmixture was diluted with EtOAc, washed with brine (2×), dried (MgSO4)and concentrated in vacuo. The residue was purified by silica gelchromatography (Hexane/EtOAc=1:0 to 85:15) to afford 1j (8.05 g).

Step 1K

To a solution of compound 1j (0.5 g, 1.4 mmol) in iso-propanol (5 ml)was added NaIO4 (0.9 g, 4.2 mmol), followed by water (5 ml). To thisvigorously stirred mixture was added OsO4 (0.4% aq. solution, 0.22 m,2.5% eq.). The resulting mixture was stirred at rt for 4 h, diluted withEtOAc, washed with aq. NaHCO3, aq. Na2S2O3, brine, dried (MgSO4) andconcentrated in vacuo. The residue was purified by silica gelchromatography (Hexane/EtOAc=1:0 to 85:15) to afford 1k (0.37 g).

Step 1L

To a solution of compound 1k (2.9 g, 8.1 mmol) in dichloromethane (25ml) at −78° C. was added diethylaminosulfur trifluoride (DAST) (2.7 ml,20.25 mmol). The resulting mixture was stirred at −78° C. for an hour,then the temperature allowed to rise gradually to rt over 6 h, dilutedwith EtOAc, washed with aq. NaHCO3 (2×), brine, dried (MgSO4) andconcentrated in vacuo. The residue was purified by silica gelchromatography (Hexane/EtOAc=1:0 to 85:15) to afford 1l (1.49 g).Recovered starting material 1k (1.2 g).

Step 1M

A solution of compound 1l (491 mg, 1.29 mmol) in dichloromethane (1 ml)was treated with 4N HCl in 1,4-dioxane (6 ml, 24 mmol.). The mixture wasstirred at room temperature for an hour, concentrated to dryness toafford 1m (˜100%).

Step 1N

To a solution of 1i (5.28 mmol), compound 1m (5.808 mmol) and DIPEA (3.6ml, 3.9 eq.) in DMF (22 ml) at 0° C. was added HATU (2.31 g, 6.07 mmol).The mixture was stirred at room temperature for 4 h, diluted with EtOAcand washed with half-sat.-aq. NaCl four times. The organic phase wasdried over anhydrous MgSO₄, filtered, and then concentrated in vacuo.The residue was purified by silica gel column (Hexane/EtOAc=9:1 to 6:4)to afford compound 1n (2.85 g). MS (ESI): m/z 706.53 (M+H).

Step 1O

To a solution of compound 1n (2.85 g, 4.04 mmol) in THF/MeOH (28 ml-12ml) at 0° C. was added lithium hydroxide monohydrate (1.02 g, 24.2 mmol)followed by water (12 ml). The mixture was stirred at room temperaturefor 2 hours, cooled to 0° C., acidified with 1N HCl to pH 5 to 6. Someorganic solvents were removed in vacuo, and the resulting mixture wasextracted with EtOAc three times (3×150 ml). The combined organicextracts were washed with brine (30 ml), dried (MgSO₄), filtered andconcentrated in vacuo to afford the title compound (˜100%). MS (ESI):m/z 678.41 (M+H).

Example 2

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

Method I

Step 2A

Ethyl ester 1l (50 g, 132 mmol) was dissolved in THF (400 mL), thenfurther diluted with MeOH (160 mL) and water (160 mL). LiOH.H₂O (27.6 g,660 mmol) was added and the reaction mixture was stirred at rtovernight. The solution was acidified to pH˜2 using 1 M HCl, thenextracted with DCM (3×500 mL). The combined organic portions were dried(Na₂SO₄), filtered, and concentrated. The crude carboxylic acid 2a wascarried directly on without any further purification.

Step 2B

Carboxylic acid 2a (˜132 mmol) was dissolved in DCM (400 mL) then cooledto 0° C. DMAP (40.3 g, 330 mmol), sulfonamide (16.0 g, 132 mmol), andEDC (63.3 g, 330 mmol) were added and reaction was stirred at 0° C. for1 h, warmed to rt, then stirred an additional 48 h. Reaction was dilutedwith EtOAC (1.5 L) and extracted with 1N HCl (2×750 mL). Combinedaqueous layers were back-extracted with EtOAc, and the combined EtOAclayers were washed with brine (1 L). Organic portions were dried(Na₂SO₄), filtered, and concentrated. Crude oil was purified via SiO₂chromatography using a 60% EtOAc/hexanes to yield the desiredsulfonimide 2b (40 g, 85%, two steps).

Step 2C

Sulfonimide 2b (40 g, 112 mmol) was directly charged with a 4M HClsolution in dioxane (282 mL, 1.13 mol), and the resulting solution wasstirred at rt for 1.5 h. The reaction mixture was concentrated in vacuo,and the crude oil dissolved in a minimum amount of DCM, and trituratedwith hexane (hexane/DCM=3.5/1.5). The solid was then filtered and driedto give 32.4 g of the targeted compound 2c.

Step 2D

To a solution of compound 1i (11 mg, 0.02 mmol), 2c (1 eq.) and DIPEA(0.05 ml, 0.287 mmol) in DMF (1 ml) at 0° C. was added HATU (24 mg,0.063 mmol). The mixture was stirred at room temperature for 18 h,diluted with EtOAc and washed with half-sat.-aq. NaCl four times. Theorganic phase was dried over anhydrous MgSO₄, filtered, and thenconcentrated in vacuo. The residue was purified by preparative HPLC toafford the title compound (6 mg). MS (ESI); m/z 781.20 (M+H).

Method II

Compound of example 1 (2.78 g, 4.04 mmol) and carbonyldiimidazole (1.11g, 6.85 mmol) were dissolved in 22 ml of anhydrous DMF and the resultingsolution was stirred at 40° C. for 1 hour. Cyclopropylsulfonamide (1.22g, 10.06 mmol) was added to the reaction followed by DBU (0.96 ml, 6.4mmol). The reaction mixture was stirred at 40° C. for 5 hours. Thereaction mixture was diluted with ethyl acetate (400 ml), washed withwater (2×50 ml), 0.5M KH₂PO₄ (2×50 ml), saturated-aqueous NaCl solution(50 ml), dried over anhydrous (MgSO4) and concentrated in vacuo. Theresidue was purified by silica gel chromatography (Hexans/EtOAc=1:1 to0:1) to give the title compound (2.4 g). MS (ESI); m/z 781.20 (M+H).

Example 3

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

Step 3A

To a solution of compound 3a-1 (21.7 g, 0.19 mole) in diethyl ether (100ml) at 5-10° C. was added dropwise LAH (1M in ether, 200 ml, 0.2 mole).The mixture was then stirred at rt for 1 h, cooled to 0-5° C. EtOAc (5ml) was added slowly, followed by careful addition of 6N HCl (200 ml),water (50 ml) and ether (50 ml). The separated aq. phase was furtherextracted with ether (2×250 ml). the combined organic layers were washedwith brine (75 ml), dried (sodium sulfate) and concentrated at 0° C. toremove ether. Distillation under reduced pressure afforded compound 3a(10.5 g).

Step 3B

To a solution of phosgene solution in toluene (20% wt. 100 ml, 188 mmol)at 10° C. was added dropwise compound 3a over 20 min. The mixture wasstirred at rt for 3 h, co-evaporated with methylene chloride (5×40 ml)to afford compound 3b (15.6 g, 77% purity).

Step 3C

To a mixture of L-tert-leucine (5.36 g, 40.8 mmol) and 1,4-dioxane (22m)was added slowly 2N NaOH while the internal temperature did not exceed30° C. The mix was cooed to 10-15° C., compound 3b (10.6 g, 77%, 49mmol) was added slowly. The mixture was stirred at rt for 15 h, then at60° C. for 3 h, cooled to rt, washed with methylene chloride (3×35 ml),The aqueous phase was adjusted to pH 2 to 3 with 6N HCl, extracted withEtOAc (3×70 ml). The combined EtOAc layers were washed with brine (20ml), dried (sodium sulfate) and concentrated to dryness to affordcompound 3c (8.3 g).

Step 3D

To a solution of compound 1d (HCl salt, 13.57 mmol), 3c (3.84 g, 14.9mmol) and DIPEA (7.1 ml, 40.7 mmol) in DMF (45 ml) at 0° C. was added inportions HATU (5.95 g, 15.6 mmol). The mixture was stirred at rt for 18h, diluted with EtOAc (400 m) and washed with water, half-sat.-aq. NaClfour times. The organic phase was dried over anhydrous Na₂SO₄, filtered,and then concentrated in vacuo. The residue was purified by silica gelchromatography (Hexane/EtOAC=9:1 to 4:1) to afford compound 3d (8.6 g).

Step 3E

A solution of compound 3d (4.04 g, 6.75 mmol) in toluene (1200 ml) waspurged with nitrogen for 0.5 h and ruthenium-based catalyst Zhan 1B (0.5g 0.675 mmol) was added. The mixture was stirred at 110° C. for 8 h,cooled to rt, 2-mercaptonicotinic acid (1.014 g, 6.7 mmo) and DIPEA (1.2ml, 6.75 mmol) were added. The mixture was stirred at rt for 16 h,filtered and concentrated. The residue was dissolved in EtOAc, washedwith aq. NaHCO₃, brine, dried (sodium sulfate). The solvent was thenevaporated and the residue was purified by silica gel flashchromatography using gradient elution (EtOAc/Hexane 0% to 25%) to yieldcompound 3e (2.6 g). MS (ESI) m/z 587.30 (M+H).

Step 3F

To a solution of compound 3e (3.1 g, 5.28 mmol) in THF/MeOH (32 ml/14ml) at 0° C. was added lithium hydroxide hydrate (1.11 g, 26.45 mmol),followed by water (14 ml). The mixture was stirred at room temperaturefor an hour, placed at 0° C., 1N HCl (˜29 ml) was added dropwise untilthe mixture's pH=˜5. The mixture was extracted with EtOAc (3×80 ml). thecombined organic layers were washed with brine (30 ml), dried (Na₂SO₄),filtered and concentrated in vacuo to afford 3f (˜100%). MS (ESI): m/z573.39 (M+H).

Step 3G

To a solution of compound 3f (16 mg, 0.028 mmol), 3g-1 (14 mg, 0.034.)and DIPEA (0.025 ml, 0.14 mmol) in DMF (1.8 ml) at 0° C. was added HATU(15 mg, 0.039 mmol). The mixture was stirred at room temperature for 2h, and purified by preparative HPLC to afford the title compound (16mg). MS (ESI): m/z 785.26 (M+H).

Example 4

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

To a solution of compound 3f (15 mg, 0.026 mmol), 4-1 (8.4 mg, 0.031.)and DIPEA (0.025 ml, 0.14 mmol) in DMF (1.8 ml) at 0° C. was added HATU(15 mg, 0.039 mmol). The mixture was stirred at room temperature for 2h, and purified by preparative HPLC to afford the title compound (15mg). MS (ESI): m/z 787.39 (M+H).

Example 5

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

To a solution of compound 3f (1.284 g, 2.07 mmol), 2c (0.681 g, 2.34mmol) and DIPEA (1.1 ml, 3 eq.) in DMF (16 ml) at 0° C. was added inportions HATU (0.914 g, 2.4 mmol). The mixture was stirred at roomtemperature for 1 h, diluted with EtOAc (180 ml), and washed with water(20 ml), half-sat.-aq. NaCl (20 ml), aq. 0.5M KH₂PO₄ (2×20 ml), brine(20 ml). The organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (EtOAc/Hexane 25% to 50%) to afford the titlecompound (1.3 g). MS (ESI); m/z 809.55 (M+H).

Example 6

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/e 767.35 (M+H).

Example 7

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/e 757.51 (M+H).

Example 8

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 771.23 (M+H).

Example 9

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 795.34 (M+H).

Example 10

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

Step 10A

To a solution of hex-5-en-1-ol (1.3 ml, 10.9 mol), triphosphogen (1.46g, 4.92 mmol) in 1,4-dioxane (21 ml) at 0° C. was added dropwise DIPEA(1.7 ml, 9.72 mmol). The mixture was stirred at room temperature for anhour, cooled to 0° C. To this was added slowly L-t-leucine (1.28 g, 9.72mmol) dissolved in 1N NaOH (9.8 ml). The resulting mixture was stirredat room temperature overnight, concentrated to remove half volume ofdioxane, treated with 1N NaOH (25 ml), washed with ether (3×30 ml). Theaqueous phase was acidified to pH 2-3 with 6N HCl, then extracted withdichloromethane (3×30 ml). The combined organic layers were dried(MgSO4), concentrated to dryness to give compound 10a (2.5 g) directlyused in next step.

Step 10B

To a solution of compound 1d (HCl salt, 98 mg, 0.218 mmol), compound 10a(90 mg, 0.35 mmol) and DIPEA (0.24 ml, 1.37 mmol) in DMF (3 ml) at 0° C.was added HATU (133 mg, 0.35 mmol). The mixture was stirred at rt for 18h, diluted with EtOAc and washed with half-sat.-aq. NaCl four times. Theorganic phase was dried over anhydrous MgSO₄, filtered, and thenconcentrated in vacuo. The resudue was purified by silica gelchromatography (Hexane/EtOAC=6:1 to 4:1) to afford compound 10b (119mg). MS (ESI): m/e 615.45 (M+H).

Step 10C

To a solution of compound 10b (119 mg, 0.19 mmol) in dichloromethane (20ml) was added Hoveyda-Grubbs' 1^(st) generation catalyst (5 mol % eq.).The reaction mixture was stirred at 40° C. for 20 h. The solvent wasthen evaporated and the residue was purified by silica gel flashchromatography using gradient elution (Hexane/EtOAC=9:1 to 7:3) to yieldthe macrocyclic compound 10c (58 mg). MS (ESI) m/z 587.44 (M+H).

Step 10D

To a solution of compound 10c (58 mg, 0.099 mmol) in THF/MeOH (3 ml/1.5ml) was added 1N lithium hydroxide (1.5 ml, 1.5 mmol). The mixture wasstirred at room temperature for 20 hours. Most organic solvents wereevaporated in vacuo, and the resulting residue was diluted with waterand acidified to pH 5 to 6. The mixture was extracted with EtOAc threetimes. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford 10d (100%). MS (ESI): m/z 573.31 (M+H),579.32 (M+Li).

Step 10E

This compound was prepared from 10d by the same procedure as describedin Example 3. MS (ESI): m/z 785.31 (M+H).

Example 11

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 795.53 (M+H).

Example 12

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 795.58 (M+H).

Example 13

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 785.29 (M+H).

Example 14

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 4. MS (ESI): m/z 787.39 (M+H).

Example 15

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/e 809.28 (M+H).

Example 16

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/e 771.11 (M+H).

Example 17

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedure as described in Example2 or Example 5. MS (ESI): m/z 795.21 (M+H).

Example 18

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 799.25 (M+H).

Example 19

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 4. MS (ESI): m/z 801.22 (M+H).

Example 20

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 823.21 (M+H).

Example 21

Compound of Formula XV, wherein R=

M-L+

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 813.42 (M+H).

Example 22

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 4. MS (ESI): m/z 815.43 (M+H).

Example 23

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 837.41 (M+H).

Example 24

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 763.25 (M+H).

Example 25

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 787.22 (M+H).

Example 26

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

Step 26A

To a solution of 26a-1 (3.4 g, 21.6 mmol), HCOOEt (3.5 ml, 43.2 mmol) inTHF (100 ml)-ether (30 ml)-pentane (30 ml) at −95° C. (liquid N2 andtoluene bath) was added dropwise n-BuLi (2.5 M in hexane, 10 ml, 25mmol). The mix. was stirred at that temperature for 1.5 h and the bathtemperature was allowed to rise gradually to 0° C. over 2-3h, quenchedwith aq. solution of NH4Cl (1.4 g in 20 ml of water). The mix. wasstirred for 15 min. To the separated organic layer was added MeOH (50ml), followed by adding NaBH₄ (1 g) in portions at 0° C. The mixture wasstirred at rt for 0.5 h, cooled to 0° C., quenched carefully with 1NHCl, to pH ˜3, extracted with ether (3×). The combined organic layerswere washed with aq. NaHCO₃, brine, dried (Na2SO4) and concentrated at0° C. The residue was purified by distillation to yield 26a (1.3 g).

Step 26B

To a solution of compound 1f (6.23 g, 11.10 mmol) in methylene chloride(100 ml) at 0° C. was added pyridine (5.4 ml, 67 mmol), followed bydropwise addition of phosgene solution (20% wt. in toluene, 17 mmol)over a period of 0.5 h. the mixture was stirred at rt for 0.5 h, dilutedwith EtOAc (500 ml), washed with water (70 ml), brine (2×70 ml), dried(sodium sulfate), filtered and concentrated to dryness to affordcompound 26b (5.3 g). MS (ESI): m/z 515.28 (M+H)

Step 26C

To a solution of compound 26b (4.89 g, 9.5 mmol) and 26a (˜1.4 eq.) inmethylene chloride (65 ml) was added molecular sieve (4 A, 5 g). Afterthe mixture was stirred at rt for 0.5 h, DBU (2.1 ml, 16=4 mmol) wasadded. The resulting mixture was stirred at rt for 2 h and concentrated.The residue was purified by silica gel flash chromatography usinggradient elution (EtOAC/Hexane 0% to 25%) to yield compound 26c (6.1 g).MS (ESI) m/z 623.34 (M+H).

Step 26D

Compound 26d was prepared from compound 26c by the same procedure asdescribed in Step 3E of example 3. MS (ESI) m/z 595.01 (M+H).

Step 26E

Compound 26e was prepared from compound 26d by the same procedure asdescribed in Step 3F of example 3. MS (ESI) m/z 581.15 (M+H).

Step 26F

Compound example 26 was prepared from 26e by the same procedures asdescribed in Example 3. MS (ESI): m/z 793.20 (M+H).

Example 27

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared from compound 26e by the same procedures asdescribed in Example 4. MS (ESI): m/z 795.43 (M+H).

Example 28

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared from compound 26e by the same procedures asdescribed in Example 5. MS (ESI): m/z 817.27 (M+H).

Example 29

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 756.23 (M+H).

Example 30

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 780.19 (M+H).

Example 31

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 3. MS (ESI): m/z 755.13 (M+H).

Example 32

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 2 or Example 5. MS (ESI): m/z 779.26 (M+H).

Example 33

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

Step 33A

A mixture of 3e (1.52 g, 2.59 mmol), Pd—C (10% wt. 182 mg) and EtOAc (38ml) was hydrogenated for 10 h, filtered and concentrated. The residuewas purified by silica gel flash chromatography using gradient elution(EtOAC4Hexane 0% to 25%) to yield compound 33a (1.3 g). MS (ESI): m/z589.27 (M+H).

Step 33B

Compound 33b was prepared from 33a by the same procedures as describedin Step 3F of Example 3. MS (ESI): m/z 575.15 (M+H).

Step 33C

Compound of example 33 was prepared from 33b by the same procedures asdescribed in Example 3. MS (ESI): m/z 778.39 (M+H).

Example 34

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared from 33b by the same procedures as describedin Example 4. MS (ESI): m/z 789.37 (M+H).

Example 35

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared from 33b by the same procedures as describedin Example 5. MS (ESI): m/z 811.26 (M+H).

Example 36

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 35. MS (ESI): m/z 769.35 (M+H).

Example 37

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 34. MS (ESI): m/z 761.62 (M+H).

Example 38

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 35. MS (ESI): m/z 783.38 (M+H).

Example 39

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 33. MS (ESI): m/z 773.49 (M+H).

Example 40

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 34. MS (ESI): m/z 775.36 (M+H).

Example 41

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 35. MS (ESI): m/z 797.34 (M+H).

Example 42

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 33. MS (ESI): m/z 787.41 (M+H).

Example 43

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 34. MS (ESI): m/z 789.26 (M+H).

Example 44

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 35. MS (ESI): m/z 811.28 (M+H).

Example 45

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 33. MS (ESI): m/z 801.57 (M+H).

Example 46

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 34. MS (ESI): m/z 803.57 (M+H).

Example 47

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 35. MS (ESI): m/z 825.50 (M+H).

Example 48

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 33. MS (ESI): m/z 815.46 (M+H).

Example 49

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 34. MS (ESI): m/z 817.46 (M+H).

Example 50

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 35. MS (ESI): m/z 839.46 (M+H).

Example 51

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

Step 51A

A mixture of 26d (2.55 g, 4.286 mmol), Pd—C (10% wt. 255 mg), DIPEA (1.5ml) and EtOAc (65 ml) was hydrogenated for 4 h, filtered andconcentrated. The residue was purified by silica gel flashchromatography using gradient elution (EtOAC/Hexane 0% to 25%) to yieldcompound 51a (1.83 g). MS (ESI): m/z 597.05 (M+H).

Step 51B

Compound 51b was prepared from compound 51a by the same procedure asdescribed in Step 3F of example 3. MS (ESI) m/z 583.04 (M+H).

Step 51C

Compound of example 51 was prepared from 51b by the same procedures asdescribed in Example 3. MS (ESI): m/z 795.27 (M+H).

Example 52

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared from 51b by the same procedures as describedin Example 4. MS (ESI): m/z 797.43 (M+H).

Example 53

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared from 51b by the same procedures as describedin Example 5. MS (ESI): m/z 819.43 (M+H).

Example 54

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=OH

This compound was prepared by the same procedures as described inExample 1. MS (ESI): m/z 680.46 (M+H).

Example 55

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

Step 55A

A solution of compound 1b (1 g, 1.9 mmol) in dichloromethane (1 ml) wastreated with 4M HCl/dioxane (6 ml, 24 mmol). The resulting mixture wasstirred at room temperature for 2 hours, and concentrated in vacuo todryness to afford HCl salt compound 55a (100%).

Step 55B

To a solution of compound 55b-1 (1.046 g, 5.5 mmol) in dichloromethane(30 ml) at 0° C. was added pyridine (2.23 ml), followed by dropwiseaddition of phosgene solution (in toluene, 20% wt., 4.4 ml, 8.3 mmol).The mixture was stirred at 0° C. for 2 h, diluted with EtOAc, washedwith 1N HCl, brine, dried (sodium sulfate) and concentrated to drynessto afford 55b (0.95 g).

Step 55C

To a solution of compound 55b (0.228 g, 1.33 mmol) and 55c-1 (1.4 g,13.3 mmol) in dichloromethane (10 ml)-DMF (2 ml) at rt was added DBU(0.3 ml, 2.18 mmo). The mixture was stirred at rt for 16 h, diluted withEtOAc, washed with water, brine twice, 1N HCl, brien, dried (sodiumsulfate) and concentrated. The residue was purified by silica gel flashchromatography using gradient elution (EtOAC/Hexane 0% to 30%) to yieldcompound 55c (0.303 g).

Step 55D

To a solution of compound 55c (0.255 g, 0.93 mmol) in THF/MeOH (6 ml/2.6ml) at 0° C. was lithium hydroxide hydrate (0.195 g, 4.6 mmol), followedby water (2.6 ml). The mixture was stirred at room temperature for 16 h,placed at 0° C., 1N HCl was added dropwise until the mixture's pH=˜3.The mixture was extracted with EtOAc three times. the combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and concentratedin vacuo to afford 55d (0.227 g).

Step 55E

To a solution of compound 55a (0.52 g, 1.1 mmol), 55d (0.93 mmol) andDIPEA (0.81 ml, 5 eq.) in DMF (8 ml) at 0° C. was added in portions HATU(0.407 g, 1.07 mmol). The mixture was stirred at room temperature for 16h, diluted with EtOAc, washed with water once, brine four times. Theorganic phase was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (EtOAc/Hexane 0% to 40%) to afford 55e (0.328 g). MS(ESI); m/z 671.32, 673.32 (M+H).

Step 55F

A mixture of compound 55e (0.161 g, 0.24 mmol), cesium carbonate (0.156g, 0.48 mmol) and toluene (10 ml) was purged with nitrogen for 5 min.Palladium acetate (11 mg, 0.049 mmol) and ligand 55f-1 (24 mg, 0.06mmol) were added. The mixture was stirred at 80° C. for 19 h, cooled tort, filtered, washed with EtOAc and concentrated. The residue waspurified by silica gel chromatography (EtOAc/Hexane 0% to 25%) to afford55f (0.035 g). MS (ESI); m/z 591.61 (M+H).

Step 55G

Compound 55g was prepared from compound 55f by the same procedure asdescribed in Step 3F of example 3. MS (ESI): m/z 577.55 (M+H).

Step 55H

Compound of example 55 was prepared from 55 g by the same procedures asdescribed in Example 3. MS (ESI): m/z 789.34 (M+H).

Example 56

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared from 55 g by the same procedures as describedin Example 4. MS (ESI): m/z 790.92 (M+H).

Example 57

Compound of Formula XV, wherein R=

M-L→

Ar=

R′=CF₂H, G=

This compound was prepared from 55 g by the same procedures as describedin Example 5. MS (ESI): m/z 813.74 (M+H).

Example 58

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 55. MS (ESI): m/z 787.20 (M+H).

Example 59

Compound of Formula XV, wherein R=

M-L

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 56. MS (ESI): m/z 789.22 (M+H).

Example 60

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 57. MS (ESI): m/z 811.59 (M+H).

Example 61

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 55. MS (ESI): m/z 807.17 (M+H).

Example 62

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 56. MS (ESI): m/z 809.10 (M+H).

Example 63

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 57. MS (ESI): m/z 831.24 (M+H).

Example 64

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 55. MS (ESI): m/z 805.14 (M+H).

Example 65

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 56. MS (ESI): m/z 807.03 (M+H).

Example 66

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 57. MS (ESI): m/z 828.97 (M+H).

Example 67

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 55. MS (ESI): m/z 797.11 (M+H).

Example 68

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=

G=

This compound was prepared by the same procedures as described inExample 56. MS (ESI): m/z 799.06 (M+H).

Example 69

Compound of Formula XV, wherein R=

M-L=

Ar=

R′=CF₂H, G=

This compound was prepared by the same procedures as described inExample 57. MS (ESI): m/z 821.54 (M+H).

Examples 70 to 1506

Compounds of Formula XV in Table 1, are made following the proceduresdescribed in Examples 1 to 69 and the Synthetic Methods section.

Examples 1507 to 1554

Compounds of Formula XVI in Table 2, are made following the proceduresdescribed in Examples 1 to 69 and the Synthetic Methods section.

Examples 1555 to 1586

Compounds of Formula XVII in Table 3, are made following the proceduresdescribed in Examples 1 to 69 and the Synthetic Methods section.

The compounds of the present invention exhibit potent inhibitoryproperties against the HCV NS3 protease. The following examples describeassays in which the compounds of the present invention can be tested foranti-HCV effects.

Example 1587 NS3/NS4a Protease Enzyme Assay

HCV protease activity and inhibition is assayed using an internallyquenched fluorogenic substrate. A DABCYL and an EDANS group are attachedto opposite ends of a short peptide. Quenching of the EDANS fluorescenceby the DABCYL group is relieved upon proteolytic cleavage. Fluorescenceis measured with a Molecular Devices Fluoromax (or equivalent) using anexcitation wavelength of 355 nm and an emission wavelength of 485 nm.

The assay is run in Corning white half-area 96-well plates (VWR29444-312 [Corning 3693]) with full-length NS3 HCV protease 1b tetheredwith NS4A cofactor (final enzyme concentration 1 to 15 nM). The assaybuffer is complemented with 10 μM NS4A cofactor Pep 4A (Anaspec 25336 orin-house, MW 1424.8). RET S1(Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser-Lys-(DABCYL)-NH₂, (SEQID NO: 4) AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptidesubstrate. The assay buffer contains 50 mM Hepes at pH 7.5, 30 mM NaCland 10 mM BME. The enzyme reaction is followed over a 30 minutes timecourse at room temperature in the absence and presence of inhibitors.

The peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8)Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, (SEQ ID NO: 5) [−20° C.] and HCV Inh 2(Anaspec 25346, MW 913.1) Ac-Asp-Glu-Dif-Cha-Cys-OH, (SEQ ID NO: 6) areused as reference compounds.

IC₅₀ values are calculated using XLFit in ActivityBase (IDBS) usingequation 205: y=A+((B−A)/(1+((C/x)^ D))).

Example 1588 Cell-Based Replicon Assay

Quantification of HCV replicon RNA (HCV Cell Based Assay) isaccomplished using the Huh 11-7 cell line (Lohmann, et al Science285:110-113, 1999). Cells are seeded at 4×10³ cells/well in 96 wellplates and fed media containing DMEM (high glucose), 10% fetal calfserum, penicillin-streptomycin and non-essential amino acids. Cells areincubated in a 7.5% CO₂ incubator at 37° C. At the end of the incubationperiod, total RNA is extracted and purified from cells using AmbionRNAqueous 96 Kit (Catalog No. AM1812). To amplify the HCV RNA so thatsufficient material can be detected by an HCV specific probe (below),primers specific for HCV (below) mediate both the reverse transcriptionof the HCV RNA and the amplification of the cDNA by polymerase chainreaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (AppliedBiosystems catalog no. 4309169). The nucleotide sequences of the RT-PCRprimers, which are located in the NS5B region of the HCV genome, are thefollowing:

HCV Forward primer “RBNS5bfor” 5′GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1): HCVReverse primer “RBNS5Brev” 5′CAAGGTCGTCTCCGCATAC. (SEQ ID NO 2)

Detection of the RT-PCR product is accomplished using the AppliedBiosystems (ABI) Prism 7500 Sequence Detection System (SDS) that detectsthe fluorescence that is emitted when the probe, which is labeled with afluorescence reporter dye and a quencher dye, is degraded during the PCRreaction. The increase in the amount of fluorescence is measured duringeach cycle of PCR and reflects the increasing amount of RT-PCR product.Specifically, quantification is based on the threshold cycle, where theamplification plot crosses a defined fluorescence threshold. Comparisonof the threshold cycles of the sample with a known standard provides ahighly sensitive measure of relative template concentration in differentsamples (ABI User Bulletin #2 Dec. 11, 1997). The data is analyzed usingthe ABI SDS program version 1.7. The relative template concentration canbe converted to RNA copy numbers by employing a standard curve of HCVRNA standards with known copy number (ABI User Bulletin #2 Dec. 11,1997).

The RT-PCR product was detected using the following labeled probe: (SEQID NO: 3) 5′FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA FAM = Fluorescencereporter dye. TAMRA := Quencher dye.

The RT reaction is performed at 48° C. for 30 minutes followed by PCR.Thermal cycler parameters used for the PCR reaction on the ABI Prism7500 Sequence Detection System are: one cycle at 95° C., 10 minutesfollowed by 40 cycles each of which include one incubation at 95° C. for15 seconds and a second incubation for 60° C. for 1 minute.

To normalize the data to an internal control molecule within thecellular RNA, RT-PCR is performed on the cellular messenger RNAglyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH copy numberis very stable in the cell lines used. GAPDH RT-PCR is performed on thesame RNA sample from which the HCV copy number is determined. The GAPDHprimers and probesare contained in the ABI Pre-Developed TaqMan AssayKit (catalog no. 4310884E). The ratio of HCV/GAPDH RNA is used tocalculate the activity of compounds evaluated for inhibition of HCV RNAreplication.

Activity of Compounds as Inhibitors of HCV Replication (Cell BasedAssay) in Replicon Containing Huh-7 Cell Lines.

The effect of a specific anti-viral compound on HCV replicon RNA levelsin Huh-1′-7 cells is determined by comparing the amount of HCV RNAnormalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposedto compound versus cells exposed to the DMSO vehicle (negative control).Specifically, cells are seeded at 4×10³ cells/well in a 96 well plateand are incubated either with: 1) media containing 1% DMSO (0%inhibition control), or 2) media/1% DMSO containing a fixedconcentration of compound. 96 well plates as described above are thenincubated at 37° C. for 4 days (EC50 determination). Percent inhibitionis defined as:% Inhibition=100−100*S/C1

where

S=the ratio of HCV RNA copy number/GAPDH RNA copy number in the sample;

C1=the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0%inhibition control (media/1% DMSO).

The dose-response curve of the inhibitor is generated by adding compoundin serial, three-fold dilutions over three logs to wells starting withthe highest concentration of a specific compound at 1.5 uM and endingwith the lowest concentration of 0.23 nM. Further dilution series (500nM to 0.08 nM for example) is performed if the EC50 value is notpositioned well on the curve. EC50 is determined with the IDBS ActivityBase program “XL Fit” using a 4-parameter, non-linear regression fit(model #205 in version 4.2.1, build 16).

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of Formula I or II:

or a pharmaceutically acceptable salt or ester thereof, wherein A isabsent or selected from —(C═O)—, —S(O)₂, —C═N—OR₁ or —C(═N—CN); L₂₀₁ isabsent or selected from —C₁-C₈ alkylene, —C₂-C₈ alkenylene, or —C₂-C₈alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S,or N; substituted —C₁-C₈ alkylene, substituted —C₂-C₈ alkenylene, orsubstituted —C₂-C₈ alkynylene each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O,S or N; —C₃-C₁₂ cycloalkenylene, or substituted —C₃-C₁₂ cycloalkenyleneeach containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; M isabsent or selected from O, S, SO, SO₂ or NR₁; wherein R₁ is selected ateach occurrence from the group consisting of: (i) hydrogen; (ii) aryl;substituted aryl; heteroaryl; substituted heteroaryl; (iii)heterocycloalkyl or substituted heterocycloalkyl; and (iv) —C₁-C₈ alkyl,—C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, orsubstituted —C₃-C₁₂ cycloalkenyl; L₁₀₁ is absent or selected from —C₁-C₈alkylene, —C₂-C₈ alkenylene, or —C₂-C₈ alkynylene each containing 0, 1,2, or 3 heteroatoms selected from O, S, or N; substituted —C₁-C₈alkylene, substituted —C₂-C₈ alkenylene, or substituted —C₂-C₈alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, Sor N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂ cycloalkylene eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂cycloalkenylene, or substituted —C₃-C₁₂ cycloalkenylene each containing0, 1, 2, or 3 heteroatoms selected from O, S or N; Z₁₀₁ is selected fromaryl, substituted aryl, heteroaryl, or substituted heteroaryl; W₁₀₁ isabsent or selected from O, S, NR₁—, —C(O)— or —C(O)NR₁—; X and Y takentogether with the carbon atoms to which they are attached to form acarbocyclic moiety or a heterocyclic moiety selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, or substituted heterocylic; or X and Y together form aC₂-C₈-alkylene group or a C₂-C₈-heteroalkylene group; R₁₀₁ and R₁₀₂ areindependently selected from the group consisting of: (i) hydrogen,halogen, CN, CF₃, N₃, NO₂, OR₁, SR₁, SO₂R₂, —NHS(O)₂—R₂, —NH(SO₂)NR₃R₄,NR₃R₄, CO₂R₁, COR₁, CONR₁R₂, N(R₁)COR₂; (ii) aryl; substituted aryl;heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl orsubstituted heterocycloalkyl; (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or—C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selected fromO, S, or N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, orsubstituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkyl; —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; Rand R′ are each independently selected from the group consisting of: (i)—C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2,or 3 heteroatoms selected from O, S, or N; substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,or substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl, orsubstituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, orsubstituted —C₄-C₁₂ alkylcycloalkenyl; (ii) aryl; substituted aryl;heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl orsubstituted heterocycloalkyl; (iv) hydrogen; deuterium; G is selectedfrom —OH, —NHS(O)₂—R₂, —NH(SO₂)NR₃R₄, and NR₃R₄; R₂ is selected from:(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl (ii)heterocycloalkyl; substituted heterocycloalkyl; and (iii) —C₁-C₈ alkyl,—C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S or N, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, orsubstituted —C₃-C₁₂ cycloalkenyl; heterocylic; substituted heterocyclic;R₃ and R₄ are independently selected from: (i) hydrogen; (ii) aryl;substituted aryl; heteroaryl; substituted heteroaryl; (iii)heterocycloalkyl or substituted heterocycloalkyl; and (iv) —C₁-C₈ alkyl,—C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, orsubstituted —C₃-C₁₂ cycloalkenyl; heterocyclic, or substitutedheterocyclic; alternatively, R₃ and R₄ are taken together with thenitrogen they are attached to form a heterocyclic or substitutedheterocyclic; Z is selected from the groups consisting of: (i) hydrogen;(ii) CN; (iii) N₃; (iv) halogen; (v) —NH—N═CHR₁; (vi) aryl, substitutedaryl; (vii) heteroaryl, substituted heteroaryl; (viii) —C₃-C₁₂cycloalkyl, substituted —C₃-C₁₂ cycloalkyl, heterocycloalkyl,substituted heterocycloalkyl; (ix) —C₁-C₆ alkyl containing 0, 1, 2, or 3heteroatoms selected from O, S, or N, optionally substituted with one ormore substituent selected from halogen, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; (x) —C₂-C₆ alkenyl containing 0,1, 2, or 3 heteroatoms selected from O, S, or N, optionally substitutedwith one or more substituent selected from halogen, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; and (xi) —C₂-C₆ alkynylcontaining 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;W is absent, or selected from alkylene, alkenylene, alkynylene, O, S,NR₁—, —C(O)NR₁—, or —C(O)—; m is 0, 1, 2 or 3; m′ is 0, 1, 2 or 3; and sis 1, 2, 3 or
 4. 2. A compound according to claim 1 wherein: M is absentor selected from O or NRi; W₁₀₁ is absent, or selected from —O—, —S—,—NH—, —N(Me)—, —C(O)NH—, and —C(O)N(Me)—; X and Y taken together withthe carbon atoms to which they are attached to form a cyclic moietywhich selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, or substituted heterocylic; R₁₀₁ and R₁₀₂ areindependently selected from the group consisting of: (i) hydrogen,halogen, CN, CF₃, NO₂, OR′, SR₁, —NHS(O)₂—R₂, —NH(SO₂)NR₃R₄, NR₃R₄,CO₂R₁, COR₁, CONR₁R₂, N(R₁)COR₂; (ii) aryl; substituted aryl;heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl orsubstituted heterocycloalkyl; (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or—C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selected fromO, S, or N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, orsubstituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkyl; —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl;R₃ and R₄ are independently selected from: (i) hydrogen; (ii) aryl;substituted aryl; heteroaryl; substituted heteroaryl; (iii)heterocycloalkyl or substituted heterocycloalkyl; (iv) —C₁-C₈ alkyl,—C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, orsubstituted —C₃-C₁₂ cycloalkenyl; heterocyclic, or substitutedheterocyclic; W is absent, or selected from alkylene, alkenylene,alkynylene, —O—, —S—, —NH—, —N(Me)—, —C(O)NH—, or —C(O)N(Me)—; m=0, 1,or 2; m′=1 or 2; and s is
 1. 3. The compound of claim 1, wherein R′ is—CHQ1Q2, wherein Q1 and Q2 are independently selected from F, Cl and Br.4. The compound of claim 1, wherein the compound is of Formula III orIV:

or a pharmaceutically acceptable salt or ester thereof.
 5. The compoundof claim 1, wherein the compound is of Formula V or VI:

or a pharmaceutically acceptable salt or ester thereof, wherein Q_(i)and Q2 are each independently selected from F, Cl and Br.
 6. Thecompound of claim 1, wherein the compound is of Formula VII:

or a pharmaceutically acceptable salt or ester thereof, where X₁-X₄ areindependently selected from —CR₅ and N, wherein: R₅ is independentlyselected from: i. hydrogen; halogen; —NO₂; —CN; N₃; CF₃; ii. -M-R₄, M isO, S, NH; iii. NR₃R₄; iv. —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, orN; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or substituted—C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selected fromO, S or N; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; v. aryl;substituted aryl; heteroaryl; substituted heteroaryl; and vi.heterocycloalkyl or substituted heterocycloalkyl.
 7. The compound ofclaim 1, wherein the compound is of Formula VIII:

or a pharmaceutically acceptable salt or ester thereof, where X₁-X₄ areindependently selected from —CR₅ and N, wherein: R₅ is independentlyselected from: i. hydrogen; halogen; —NO₂; —CN; N₃; CF₃; ii. -M-R₄, M isO, S, NH; iii. NR₃R₄; iv. —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, orN; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or substituted—C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selected fromO, S or N; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; v. aryl;substituted aryl; heteroaryl; substituted heteroaryl; and vi.heterocycloalkyl or substituted heterocycloalkyl; Q_(i) and Q2 are eachindependently selected from F, Cl and Br.
 8. The compound of claim 1,wherein the compound is of Formula IX:

or a pharmaceutically acceptable salt or ester thereof, wherein: Y₁-Y₃are independently selected from CR₅, N, NR_(S), S and O; R₅ isindependently selected from: i. hydrogen; halogen; —NO₂; —CN; N₃; CF₃;ii. -M-R₄, M is O, S, NH; iii. NR₃R₄; iv. —C₁-C₈ alkyl, —C₂-C₈ alkenyl,or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selectedfrom O, S, or N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl,or substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkyl; —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl;v. aryl; substituted aryl; heteroaryl; substituted heteroaryl; and vi.heterocycloalkyl or substituted heterocycloalkyl.
 9. The compound ofclaim 1, wherein the compound is of Formula X:

or a pharmaceutically acceptable salt or ester thereof, wherein: Y₁, Y₂and Y₃ are independently selected from CR₅, N, NR₅, S and O; R₅ isindependently selected from: i. hydrogen; halogen; —NO₂; —CN; N₃; CF₃;ii. -M-R₄, M is O; S, NH; iii. NR₃R₄; iv. —C₁-C₈ alkyl, —C₂-C₈ alkenyl,or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selectedfrom O, S, or N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl,or substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkyl; —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl;v. aryl; substituted aryl; heteroaryl; substituted heteroaryl; and vi.heterocycloalkyl or substituted heterocycloalkyl; and Q1 and Q2 are eachindependently fluorine, chlorine or bromine.
 10. The compound of claim1, wherein the compound is of Formula XI:

or a pharmaceutically acceptable salt or ester thereof.
 11. The compoundof claim 1, wherein the compound is of Formula XII:

or a pharmaceutically acceptable salt or ester thereof, where Q_(i) andQ2 are independently fluorine, chlorine or bromine.
 12. The compound ofclaim 1, wherein the compound is of Formula XIII:

or a pharmaceutically acceptable salt or ester thereof, wherein W₁ isabsent or selected from C₁-C₄ alkylene, C₂-C₄ alkenylene, and C₂-C₄alkynylene.
 13. The compound of claim 1, wherein the compound is ofFormula XIV:

or a pharmaceutically acceptable salt or ester thereof, wherein W₁ isabsent or selected from C₁-C₄ alkylene, C₂-C₄ alkenylene, and C₂-C₄alkynylene; and Q1 and Q2 are independently fluorine, chlorine orbromine.
 14. A compound according to claim 1 which is selected fromcompounds of Formula XV,

or a pharmaceutically acceptable salt or ester thereof, wherein R, M-L,Ar, R′ and G are set forth for each compound in the table below: TABLE 1Example # R M—L Ar R′ G 1

OH 2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

OH 55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

OH 334

OH 335

OH 336

OH 337

OH 338

OH 339

OH 340

OH 341

OH 342

OH 343

OH 344

OH 345

OH 346

OH 347

OH 348

OH 349

OH 350

OH 351

OH 352

OH 353

OH 354

OH 355

OH 356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

OH 630

OH 631

OH 632

OH 633

OH 634

OH 635

OH 636

OH 637

OH 638

OH 639

OH 640

OH 641

OH 642

OH 643

OH 644

OH 645

OH 646

OH 647

OH 648

OH 649

OH 650

OH 651

OH 652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

OH 932

OH 933

OH 934

OH 935

OH 936

OH 937

OH 938

OH 939

OH 940

OH 941

OH 942

OH 943

OH 944

OH 945

OH 946

OH 947

OH 948

OH 949

OH 950

OH 951

OH 952

OH 953

OH 954

OH 955

OH 956

957

OH 958

959

OH 960

961

OH 962

963

OH 964

965

OH 966

967

OH 968

969

OH 970

971

OH 972

973

OH 974

975

OH 976

977

OH 978

979

OH 980

981

OH 982

983

OH 984

985

OH 986

987

OH 988

989

OH 990

991

OH 992

993

OH 994

995

OH 996

997

OH 998

999

OH 1000

1001

OH 1002

1003

OH 1004

1005

OH 1006

1007

OH 1008

1009

OH 1010

1011

OH 1012

1013

OH 1014

1015

OH 1016

1017

OH 1018

1019

OH 1020

1021

OH 1022

1023

OH 1024

1025

OH 1026

1027

OH 1028

1029

OH 1030

1031

OH 1032

1033

OH 1034

1035

OH 1036

1037

OH 1038

1039

OH 1040

1041

OH 1042

1043

OH 1044

1045

OH 1046

1047

OH 1048

1049

OH 1050

1051

OH 1052

1053

OH 1054

1055

OH 1056

1057

OH 1058

1059

OH 1060

1061

OH 1062

1063

OH 1064

1065

OH 1066

1067

OH 1068

1069

OH 1070

1071

OH 1072

1073

OH 1074

1075

OH 1076

1077

OH 1078

1079

OH 1080

1081

OH 1082

1083

OH 1084

1085

OH 1086

1087

OH 1088

1089

OH 1090

1091

OH 1092

1093

OH 1094

1095

OH 1096

1097

OH 1098

1099

OH 1100

1101

OH 1102

1103

OH 1104

1105

OH 1106

1107

OH 1108

1109

OH 1110

1111

OH 1112

1113

OH 1114

1115

OH 1116

1117

OH 1118

1119

OH 1120

1121

OH 1122

1123

OH 1124

1125

OH 1126

1127

OH 1128

1129

OH 1130

1131

OH 1132

1133

OH 1134

1135

OH 1136

1137

OH 1138

1139

OH 1140

1141

OH 1142

1143

OH 1144

1145

OH 1146

1147

OH 1148

1149

OH 1150

1151

OH 1152

1153

OH 1154

1155

OH 1156

1157

OH 1158

1159

OH 1160

1161

OH 1162

1163

OH 1164

1165

OH 1166

1167

OH 1168

1169

OH 1170

1171

OH 1172

1173

OH 1174

1175

OH 1176

1177

OH 1178

1179

OH 1180

1181

OH 1182

1183

OH 1184

1185

OH 1186

1187

OH 1188

1189

OH 1190

1191

OH 1192

1193

OH 1194

1195

OH 1196

1197

OH 1198

1199

OH 1200

1201

OH 1202

1203

OH 1204

1205

OH 1206

1207

OH 1208

1209

OH 1210

1211

OH 1212

1213

OH 1214

1215

OH 1216

1217

OH 1218

1219

OH 1220

1221

OH 1222

1223

OH 1224

1225

OH 1226

1227

OH 1228

1229

OH 1230

1231

OH 1232

1233

OH 1234

1235

OH 1236

1237

OH 1238

1239

OH 1240

1241

OH 1242

1243

OH 1244

OH 1245

1246

1247

OH 1248

OH 1249

1250

1251

1252

1253

OH 1254

OH 1255

1256

1257

1258

1259

1260

1261

1262

1263

OH 1264

OH 1265

1266

1267

1268

1269

1270

1271

OH 1272

1273

1274

1275

1276

OH 1277

1278

1279

1280

1281

1282

1283

1284

1285

1286

1287

OH 1288

OH 1289

1290

1291

OH 1292

OH 1293

1294

1295

1296

1297

OH 1298

OH 1299

1300

1301

1302

1303

1304

1305

1306

1307

OH 1308

OH 1309

1310

1311

1312

1313

1314

1315

1316

1317

1318

1319

1320

1321

1322

1323

1324

1325

1326

1327

1328

1329

1330

1331

1332

1333

1334

1335

1336

1337

1338

1339

1340

1341

1342

1343

1344

1345

1346

1347

1348

1349

1350

1351

1352

1353

1354

1355

1356

1357

1358

1359

1360

1361

1362

1363

1364

1365

1366

1367

1368

1369

1370

1371

1372

1373

1374

1375

1376

1377

1378

1379

1380

1381

1382

1383

1384

1385

1386

1387

1388

1389

1390

1391

1392

1393

1394

1395

1396

1397

1398

1399

1400

1401

1402

1403

1404

1405

1406

1407

1408

1409

1410

1411

1412

1413

1414

1415

1416

1417

1418

1419

1420

1421

1422

1423

1424

1425

1426

1427

1428

1429

1430

1431

1432

1433

1434

1435

1436

1437

1438

1439

1440

1441

1442

1443

1444

1445

1446

1447

1448

1449

1450

1451

1452

1453

1454

1455

1456

1457

1458

1459

1460

1461

1462

1463

1464

1465

1466

1467

1468

1469

1470

1471

1472

1473

1474

1475

1476

1477

1478

1479

1480

1481

1482

1483

1484

1485

1486

1487

1488

1489

1490

1491

1492

1493

1494

1495

1496

1497

1498

1499

1500

1501

1502

1503

1504

1505

1506


15. A compound according to claim 1 which is selected from compounds ofFormula XVI wherein R, L-Ar, R′ and G are set forth in the table below:TABLE 2 (XVI)

Compound # R L-Ar n R′ G 1507

4

1508

4

1509

4

1510

3

1511

3

1512

3

1513

2

1514

2

1515

2

1516

1

1517

1

1518

1

1519

4

1520

4

1521

4

1522

3

1523

3

1524

3

1525

2

1526

2

1527

2

1528

1

1529

1

1530

1

1531

4

1532

4

1533

4

1534

3

1535

3

1536

3

1537

2

1538

2

1539

2

1540

1

1541

1

1542

1

1543

4

1544

4

1545

4

1546

3

1547

3

1548

3

1549

2

1550

2

1551

2

1552

1

1553

1

1554

1

.


16. A compound according to claim 1 which is selected from compounds ofFormula XVII wherein R, L-Ar, and G are set forth in the table below:TABLE 3 (XVII)

Compound # R L-Ar n G 1555

4

1556

4

1557

3

1558

3

1559

2

1560

2

1561

1

1562

1

1563

4

1564

4

1565

3

1566

3

1567

2

1568

2

1569

1

1570

1

1571

4

1572

4

1573

3

1574

3

1575

2

1576

2

1577

1

1578

1

1579

4

1580

4

1581

3

1582

3

1583

2

1584

2

1585

1

1586

1

.


17. A pharmaceutical composition comprising a compound according toclaim 1 or a pharmaceutically acceptable salt or ester thereof, incombination with a pharmaceutically acceptable carrier or excipient. 18.A method of treating hepatitis C virus infection in a subject,comprising administering to the subject an inhibitory amount of apharmaceutical composition according to claim
 17. 19. A method ofinhibiting the replication of hepatitis C virus, the method comprisingadministering a hepatitis C viral NS3 protease inhibitory amount of thepharmaceutical composition of claim
 17. 20. The method of claim 18further comprising administering concurrently an additionalanti-hepatitis C virus agent.
 21. The method of claim 20, wherein saidadditional anti-hepatitis C virus agent is selected from the groupconsisting of α-interferon, β-interferon, ribavirin, and adamantine. 22.The method of claim 19, wherein said additional anti-hepatitis C virusagent is an inhibitor of hepatitis C virus helicase, polymerase,metalloprotease, or IRES.
 23. The pharmaceutical composition of claim17, further comprising another anti-HCV agent.
 24. The pharmaceuticalcomposition of claim 17, further comprising an agent selected frominterferon, ribavirin, amantadine, another HCV protease inhibitor, anHCV polymerase inhibitor, an HCV helicase inhibitor, or an internalribosome entry site inhibitor.
 25. The pharmaceutical composition ofclaim 17, further comprising pegylated interferon.
 26. Thepharmaceutical composition of claim 17, further comprising anotheranti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or animmune modulator.
 27. The composition of claim 17, further comprising acytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptablesalt thereof.
 28. The composition of claim 27, wherein the cytochromeP450 monooxygenase inhibitor is ritonavir.
 29. A method of treating ahepatitis C viral infection in a patient in need thereof, comprisingco-administering to the patient a cytochrome P450 monooxygenaseinhibitor or a pharmaceutically acceptable salt thereof and a compoundas set forth in claim 1 or a pharmaceutically acceptable salt or esterthereof.